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Gut Microbiome and Checkpoint Inhibitor Response
Does the composition of the gut microbiome influence the response of cancer patients to immune checkpoint inhibitors?
How this review was searched
267 papers found, the 80 closest to the question screened on their abstract, 78 judged relevant, 30 included. Published from 2018 to 2024. 12 founding papers, 6 from the last three years, 22 reviews.
Published in a journal or proceedings: 30 · preprints: 0 · deposits nobody reviewed: 0. The conclusions of 18 open full texts were read too.
17 of the 17 findings are backed by a sentence found word for word in a paper. So are 4 of the 5 points of agreement, disagreement and gaps.
An exploratory synthesis, not a systematic review: the papers are read from their abstracts and the conclusions of their open full texts, and papers that OpenAlex and arXiv do not index, or that our searches word differently, can be missing.
Searches and sources
Inclusion: Include human and preclinical studies, clinical trials, and reviews that examine gut microbiome composition or microbiome-directed interventions in relation to immune checkpoint inhibitor response, outcomes, or proposed mechanisms in cancer.
Key concepts: Gut microbiome composition, Cancer response to immune checkpoint inhibitors, Proposed mechanisms, Research methods and clinical settings
Queries:
- gut microbiome checkpoint inhibitors
- intestinal microbiota immunotherapy response
- microbial metabolites antitumor immunity
- microbiome checkpoint blockade resistance
- fecal microbiota transplantation cancer immunotherapy
- metagenomic cohort cancer immunotherapy
- OpenAlex, by relevance: 136
- OpenAlex, last three years: 82
- arXiv: 1
- OpenAlex, reviews: 15
- OpenAlex, most cited: 25
- Cited by several of the closest papers: 50 (10 abstracts found on Semantic Scholar or arXiv)
- Recent papers citing the founding ones: 25
A paper found by several searches is counted in each.
In short
The papers support a relationship between gut microbiome composition and response to immune checkpoint inhibitors (ICIs), but human evidence is predominantly observational and does not establish a universally causal or clinically predictive microbial signature. [6][11][13][15][19][22] Associations extend across melanoma, lung cancer, gastrointestinal cancers and hepatobiliary cancers, although the implicated organisms and the importance of microbial diversity vary between cohorts. [6][8][11][13][15][19] Proposed mechanisms include microbial effects on dendritic cells, effector T cells and other immune populations, antigen cross-reactivity, and metabolites that connect intestinal microbial activity to systemic and intratumoral immunity. [14][16][21] Animal transfer experiments and early human fecal microbiota transplantation studies strengthen the case for a modifiable relationship, but the supplied reviews call for prospective interventional validation rather than routine microbiome-directed treatment. [10][16][17] Recent studies suggest that treatment regimen, strain-level resolution, geography, concomitant medications and changes during treatment help explain inconsistent signatures; all supplied papers are identified as published journal articles, not unreviewed preprints or deposits. [19][22][25][29]
This summary rests on the findings below, each with the sentences that support it.
Approaches compared
| Approach | Papers | Strengths | Limits |
|---|---|---|---|
| Broad synthesis of microbiome–ICI associations and their methodological limitations | [1][2][3][4][5][7][10][20][24][26][28] | This approach integrates evidence across cancers, experimental systems and treatment strategies while identifying recurring methodological problems. | These reviews largely synthesize overlapping underlying studies and therefore should not be counted as independent confirmations of clinical effects. |
| Immune and metabolic mechanisms connecting the intestine to tumors | [14][16][18][21][27][30] | Mechanistic integration explains how an intestinal community could affect distant tumors and why microbial interventions might alter both efficacy and toxicity. | The mechanisms remain incompletely characterized, and much of their support comes from preclinical or preliminary clinical work rather than definitive human mechanistic interventions. |
| Clinical cohorts across cancer types and metabolite measurements | [6][8][9][13][15] | These studies test clinical relevance in distinct populations and connect stool measurements with treatment outcomes and, in some cases, immune or metabolic measurements. | Their observational designs cannot establish microbial causation, and small samples, selection effects and heterogeneous cancers or treatments constrain transportability. |
| Cross-cohort reproducibility, strain resolution and longitudinal profiling | [11][12][19][22][25][29] | Cross-cohort validation and longitudinal analysis directly test generalizability and reveal information hidden by single-cohort baseline comparisons. | Predictive associations remain sensitive to confounding, batch correction, regimen and sampling time, and do not themselves demonstrate that changing the identified organisms changes outcomes. |
| Microbiome modulation as an experimental clinical strategy | [17][23] | Interventional work directly addresses whether microbiome modification could restore sensitivity rather than merely mark favorable prognosis. | The early clinical evidence is concentrated in a narrow melanoma setting and does not establish routine safety, comparative efficacy or applicability across ICI regimens and cancers. |
Broad synthesis of microbiome–ICI associations and their methodological limitations
These reviews frame the gut microbiome as a contributor to heterogeneous ICI outcomes through its interactions with host immunity. They also emphasize that promising associations have not resolved which microbial communities should be targeted, how microbiome measurements should be standardized, or how findings should enter clinical practice.
- The reviews converge on a relationship between intestinal microbes and ICI efficacy, drawing on both experimental models and patient studies rather than independent new clinical datasets. [1][20]
“In xenograft model, bacteria in gut have been proved as a crucial factor regulating immunotherapy efficacy.” [1]
1 more supporting sentence
“A prime example is seen in immunotherapy, for which gut microbes determine the therapeutic responses associated with immune checkpoint inhibitors (ICIs) in preclinical models and patient cohorts.” [20]
- Antibiotic exposure is associated with diminished ICI efficacy in this literature, although the optimal clinical approach to antibiotic selection and timing remains unresolved. [4][28]
“Efficacy of cancer immunotherapy with immune checkpoint antibodies can be diminished with administration of antibiotics, and superior efficacy is observed with the presence of specific gut microbes.” [4]
1 more supporting sentence
“Therefore, future studies should focus on developing evidence-based guidelines for antibiotic administration during ICI therapy.” [28] · full text
- Inconsistent findings and variation in sampling, sequencing and analysis prevent straightforward validation of the microbiome as a predictive biomarker. [7]
“Among these, a better understanding of the immunomodulatory function of the microbiome, standardization in sampling, sequencing techniques, and data analysis, and ensuring uniformity across various aspects of study design are warranted in conducting future prospective studies seeking to validate the gut microbiome as a potential biomarker of response to checkpoint blockade.” [7]
Immune and metabolic mechanisms connecting the intestine to tumors
Mechanistic reviews describe several interacting routes through which microbes could alter ICI activity, including innate immune sensing, antigen-specific cross-reactivity and circulating metabolites. Their common endpoint is a change in the tumor immune environment, but the same microbial–immune interactions may also influence immune-related toxicity.
- Favorable microbiota modulation is linked to greater intratumoral CD8+ effector T-cell infiltration, often accompanied by greater T-helper type 1 and dendritic-cell activity and fewer immunosuppressive cells. [14]
“Preclinical and preliminary clinical findings from numerous types of gut microbiota modulation studies, including fecal transplantation, probiotics, consortia, and diet, demonstrate that favorable microbiota modulation is associated with increased intratumoral infiltration of CD8+ effector T cells.” [14]
- Shared microbial and tumor epitopes provide an antigen-specific mechanism that could either enhance or reduce antitumor responses rather than uniformly improving them. [16]
“Antigen-specific mechanisms occur when epitopes are shared between microbial and tumor antigens that could enhance, or, alternatively, reduce anti-tumor immune responses via cross-reactive adaptive immune cells.” [16]
- Microbial metabolites are proposed to transmit intestinal signals to local and systemic antitumor immune responses, although the supplied evidence does not establish one universally beneficial metabolite pathway. [21]
“Notably, one of the primary modes by which the gut microbiota modulate antitumor immunity is by means of metabolites, which are small molecules that could spread from their initial location of the gut and impact local and systemic antitumor immune response to promote ICI efficiency.” [21]
- Microbes associated with ICI sensitivity may also increase immune-related adverse-event risk, so efficacy and safety cannot be assumed to improve together. [18]
“Emerging data have shown that certain bacterial strains, such as Faecalibacterium that confer sensitivity to ICPI, also have a higher propensity to increase the risk of irAEs.” [18]
Clinical cohorts across cancer types and metabolite measurements
Observational studies extend the association beyond melanoma into East Asian lung-cancer cohorts, gastrointestinal malignancies and hepatobiliary cancers. They identify candidate taxa, immune correlates and metabolic features, but their modest sample sizes and different clinical settings limit generalization.
- In one study of 37 Chinese patients with advanced NSCLC receiving nivolumab, higher baseline microbial diversity was associated with response, longer progression-free survival and peripheral memory T-cell and natural-killer-cell signatures. [6]
“Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491).” [6]
- A separate retrospective study of 17 Japanese patients with NSCLC found a tendency toward longer time to treatment failure with abundant Lactobacillus and Clostridium, but enrollment required more than three months of ICI treatment. [8]
“In this retrospective study, we included 17 Japanese patients with advanced NSCLC who were treated with ICIs for >3 months in our hospital.” [8]
- A single prospective cohort of 52 patients with solid tumors linked higher concentrations of several fecal short-chain fatty acids to longer progression-free survival during PD-1 inhibition, supporting a metabolic association rather than proving that supplementation improves outcomes. [9]
“Among 52 patients enrolled, the median (range) patient age was 67 (27-84) years, and 23 (44%) were women.” [9]
- GI and hepatobiliary cohorts linked clinical benefit to microbial functional features, including SCFA-production potential in GI cancers and energy-metabolism annotations in hepatobiliary cancers. [13][15]
“Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti–PD-1/PD-L1 response across different GI cancer types.” [13]
1 more supporting sentence
“Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers.” [15]
Cross-cohort reproducibility, strain resolution and longitudinal profiling
These studies test whether microbial associations survive adjustment, external validation and repeated sampling rather than merely separating responders within one dataset. They support a microbiome signal while showing that its reproducibility depends on analytical resolution, clinical context and treatment timing.
- In one 25-patient melanoma study, responders and nonresponders did not differ significantly in alpha-diversity, and adjustment for age, BMI and antibiotic use was important for interpreting taxonomic associations. [11]
“We observed no significant differences in alpha-diversity and bacterial prevalence between responders and non-responders (P > 0.05).” [11]
- A four-study meta-analysis found candidate shared features but only modest, imprecise independent discrimination, while a larger cross-cohort analysis found no single fully consistent species biomarker. [12][19]
“A classifier designed to predict responders based on these features identified responders in an independent cohort of 27 patients with the area under the receiver operating characteristic curve of 0.625 (95% CI: 0.348-0.899) and was predictive of prognosis (HR = 0.35, P = 0.081).” [12]
1 more supporting sentence
“Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies.” [19]
- One integrated melanoma analysis improved cross-cohort prediction using batch-corrected data, while one later cross-cancer study found that strain signatures generalized only between cohorts receiving concordant ICB regimens. [22][25]
“Despite between-cohort heterogeneity, optimized all-minus-one supervised learning algorithms trained on batch-corrected microbiome data consistently predicted outcomes to programmed cell death protein-1 therapy in all cohorts.” [22]
1 more supporting sentence
“Through a meta-analysis of gut metagenomes from a further six comparable studies (n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain-response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4).” [25]
- A single longitudinal study of 175 patients with melanoma showed that many discriminatory microbial features emerged only after treatment initiation, indicating that baseline sampling alone misses outcome-associated dynamics. [29]
“Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12).” [29]
Microbiome modulation as an experimental clinical strategy
The translational reviews discuss FMT, probiotics, prebiotics and diet as ways to move from association toward intervention. Early FMT results in anti-PD-1-refractory melanoma are encouraging, but neither general effectiveness nor optimal microbial products and delivery strategies are established.
- A clinical review reports improved responses without added toxicity in two early studies using responder-derived FMT in patients with anti-PD-1-refractory metastatic melanoma, but calls for robust randomized trials. [17]
“Two studies showed that patients with anti-PD-1 refractory metastatic melanoma experienced improved response rates and no added toxicity when receiving fecal microbiota transplant (FMT) from patients with anti-PD-1 responsive disease.” [17]
- The 2023 probiotics review states that no probiotic had FDA approval for use with immunotherapy and identifies strain-level discrimination between helpful and harmful bacteria as a prerequisite for development. [23]
“Although probiotics are traditionally being supplemented to promote treatments or sustain therapeutic benefits; the FDA has not approved any for use with immunotherapy.” [23]
Where the papers agree
- The microbiome–response association is credible, but a simple universal species-based biomarker is not supported by the cross-cohort evidence. [19][25]
2 supporting sentences
“A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts.” [19]
“Studies suggest that there is a relationship between a cancer patient's gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging.” [25]
- Clinical microbiome targeting remains investigational and requires better controlled prospective testing. [5][16]
2 supporting sentences
“It is unclear that which specific composition of the gut microbiome is most conducive to promoting an anti-tumor immune response, and there are a variety of treatments that alter the microbiome, which requires careful testing in the setting of clinical trials.” [5] · full text
“To establish microbiome-based biomarkers of outcomes and specifically modulate the intestinal microbiome to enhance efficacy of ICIs in cancer immunotherapy, further prospective interventional studies will be required.” [16]
What they leave open
- Whether greater microbial diversity is independently beneficial remains unresolved; positive cohort findings should not be generalized into a universal rule. [12]
1 supporting sentence
“In fact, the importance of community diversity in ICI outcomes remains to be determined.” [12] · full text
- The optimal timing, form and duration of microbiome modification have not been established. [18]
No paper states it in these words: inferred from what the papers do not study. Check it.
- Larger studies need to integrate clinical factors and repeated microbiome measurements rather than treating baseline composition as an isolated predictor. [19][29]
2 supporting sentences
“Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.” [19]
“Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy.” [29]
Often cited, not read
Several of the papers found cite these works, but no abstract of them could be found: they are not in the synthesis. Read them if they are not already known to you.
- Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab
- A defined commensal consortium elicits CD8 T cells and anti-cancer immunity
- Enterococcus hirae and Barnesiella intestinihominis Facilitate Cyclophosphamide-Induced Therapeutic Immunomodulatory Effects
- Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial
- Diet-driven microbial ecology underpins associations between cancer immunotherapy outcomes and the gut microbiome
References
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[1] Gut microbiome modulates efficacy of immune checkpoint inhibitors
Review Microbiome modulation review · review
Why it is here: Reviews evidence and mechanisms connecting gut microbiome composition with checkpoint inhibitor efficacy.
Abstract · conclusions of the full text read too
Immune checkpoint inhibitors (ICIs) therapy is a novel strategy for cancer treatments in recent years. However, it was observed that most patients treated with ICIs could not get benefit from the therapy, which led to the limitation of clinical application. Motivated by potent and durable efficacy of ICIs, oncologists endeavor to explore the mechanisms of resistance to ICIs and increase the drug sensitivity. It is known that heterogeneity of gut microbiome in populations may result in different outcomes of therapy. In xenograft model, bacteria in gut have been proved as a crucial factor regulating immunotherapy efficacy. And the similar phenomenon was obtained in patients. In this review, we summarized relevant advancements about gut microbiome and ICIs. Furthermore, we focused on modulatory function of gut microbiome in ICIs therapy and possible antitumor mechanism of specific commensals in ICIs treatment. We propose that gut microbiome is an important predictive factor, and manipulation of gut microbiome is feasible to elevate response rate in ICIs therapy.
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[2] Microbiota and cancer immunotherapy: in search of microbial signals
Founding Review review of microbial signals · review
Why it is here: Discusses microbial features and therapeutic approaches relevant to cancer immunotherapy.
Abstract
The intestinal microbiota, a conglomerate of microorganisms comprising bacteria, viruses, archaea and fungi, has been recognised as an important component of host physiology through, for example, its influence on nutritional biotransformation, immune response and xenobiotic metabolism.1 These functions are performed via a complexed and multilayer set of controls coming from within the microbial community as well as host factors. Consequently, this intricate microbiota–host partnership is viewed as an essential element of health. For example, intestinal bacterial, fungal and viral composition is different in patients with IBDs and colorectal cancer compared with healthy subjects.2–4 A number of investigative lines probing the impact of microbiota in disease initiation, progression and therapeutics are currently underway. The microbial therapeutic field is particularly dynamic, in part due to the impressive success of faecal microbiota transplantation (FMT) for treatment of recurrent Clostridium difficile infection.5 Whether FMT or derivative synthetic cocktail could be applied to other disease conditions is unclear, and a number of clinical trials for the treatment of metabolic syndrome, diabetes and IBD are currently underway to address this question. The field of cancer has been particularly attentive to the interaction between bacteria and therapeutics.6 7 This impact of bacteria on therapeutics is wide and includes modulation of chemotherapeutic and immunotherapeutic agents’ efficacy and toxicity via metabolic and immune-mediated mechanisms.8–11 In particular, the recent discovery that intestinal microbiota profoundly impacts responses of patients with cancer to immune checkpoint blockade therapy (Routy et al ,12 Gopalakrishnan et al 13 and Matson et al 14) has attracted much attention. In these studies, the authors used an antibody targeting the coinhibitory receptor/ligand system programmed death-1 (PD-1)/PDL-1 administered to patients with metastatic melanoma13 14 or non-small cell lung cancer and renal cell carcinoma.12 The overall hypothesis pursued by these research teams was …
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[3] The Influence of the Gut Microbiome on Cancer, Immunity, and Cancer Immunotherapy
Founding Review Microbiome and immunotherapy review · review
Why it is here: Provides broad context on microbiome effects on cancer immunity and treatment response.
Abstract
The microbiome is receiving significant attention given its influence on a host of human diseases including cancer. Its role in response to cancer treatment is becoming increasingly apparent, with evidence suggesting that modulating the gut microbiome may impact responses to numerous forms of cancer therapy. A working knowledge of the microbiome is vital as we move forward in this age of precision medicine, and an understanding of the microbiome’s influence on immune responses and cancer is key. It is also important to understand factors influencing the gut microbiome and strategies to manipulate the microbiome to augment therapeutic responses.
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[4] The microbiome in cancer immunotherapy: Diagnostic tools and therapeutic strategies
Founding Review Diagnostic and therapeutic review · review
Why it is here: Discusses microbiome diagnostics and interventions, including evidence that antibiotics can impair checkpoint immunotherapy.
Abstract
The fine line between human health and disease can be driven by the interplay between host and microbial factors. This "metagenome" regulates cancer initiation, progression, and response to therapies. Besides the capacity of distinct microbial species to modulate the pharmacodynamics of chemotherapeutic drugs, symbiosis between epithelial barriers and their microbial ecosystems has a major impact on the local and distant immune system, markedly influencing clinical outcome in cancer patients. Efficacy of cancer immunotherapy with immune checkpoint antibodies can be diminished with administration of antibiotics, and superior efficacy is observed with the presence of specific gut microbes. Future strategies of precision medicine will likely rely on novel diagnostic and therapeutic tools with which to identify and correct defects in the microbiome that compromise therapeutic efficacy.
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[5] Gut microbiome and cancer immunotherapy
Review Cancer immunotherapy review · review
Why it is here: Discusses evidence that the gut microbiome affects cancer immunotherapy efficacy, especially checkpoint inhibitors.
Abstract · conclusions of the full text read too
Microbiome is becoming crucial in that the balance between human health and disease can be mediated by the gut microbiome. The gut microbiome can modulate the host immune system both locally and systemically. Cancer immunotherapy has emerged as a promising way in the treatment of patients with cancer. Accumulating evidence supports that microbiome affects the therapeutic efficacy of cancer immunotherapy, particularly immune checkpoint inhibitors. Here, we discuss the mutual relationship among gut microbiome, cancer, immunity, and cancer immunotherapy, with a focus on immunotherapy. Also, we briefly introduce the relevant challenges that affect the therapeutic efficacy and present the possible solutions. • Microbiome plays a key role in human health and disease, and gut microbiome affects immunity both locally and systemically. • Gut microbiome affects the efficacy of cancer immunotherapy, especially ICIs involving blockade of PD-1 or PD-L1 and CTLA-4. • Despite the potential of gut microbiome in immunotherapy, some challenges remain, including selection of an optimal FMT donor.
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Founding 16S longitudinal patient study · observational study
Why it is here: Tests associations between gut microbiome diversity and anti-PD-1 outcomes in Chinese NSCLC patients.
Abstract
INTRODUCTION Gut microbiome affecting the responses to immune checkpoint inhibitors against advanced NSCLC has been investigated in the Western population. However, considering pre-existing genetic and gut microbiota variation, the relevance remains unknown in the East-Asian NSCLC population. This study is designed to explore the relationship between gut microbiome and clinical outcomes in Chinese patients with NSCLC who have received treatment using an anti-programmed death 1 (PD-1) blockade. METHODS Thirty-seven patients with advanced NSCLC receiving treatment with nivolumab were enrolled in CheckMate 078 (NCT02613507) and CheckMate 870 (NCT03195491). Fecal samples were collected at the starting point, when patients received nivolumab, at clinical evaluation, and when disease progression was noted. 16S ribosome RNA gene sequencing was applied to assess gut microbiota profiles. Peripheral immune signatures were determined by multicolor flow cytometry in parallel. RESULTS When subgrouping patients into responder (R) and nonresponder according to the clinical response assessed using Response Evaluation Criteria in Solid Tumor version 1.1, R patients harbored higher diversity of gut microbiome at the starting point with stable composition during the treatment. Patients with high microbiome diversity had significantly prolonged progression-free survival when compared to those with low diversity. Compositional difference was observed between the two groups as well with the enrichment of Alistipes putredinis, Bifidobacterium longum, and Prevotella copri in R whereas Ruminococcus_unclassified enriched in nonresponding patients. Analysis of systemic immune responses using multicolor flow cytometry revealed that patients with a high abundance of microbiome diversity in the gut had a greater frequency of unique memory CD8+ T cell and natural killer cell subsets in the periphery in response to anti-PD-1 therapy. CONCLUSIONS Our results reveal strong correlation between gut microbiome diversity and the responses to anti-PD-1 immunotherapy in Chinese patients with advanced NSCLC. Patients with favorable gut microbiome (such as those with high diversity) exhibit enhanced memory T cell and natural killer cell signatures in the periphery. These findings provide important implications for the prediction and the evaluation of anti-PD-1 immunotherapy against NSCLC in the Chinese population.
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[7] The gut microbiome and response to immune checkpoint inhibitors: preclinical and clinical strategies
Founding Review Preclinical and clinical evidence review · review
Why it is here: Reviews evidence linking gut microbiome composition with checkpoint inhibitor efficacy and discusses unresolved issues.
Abstract · conclusions of the full text read too
There is growing interest in identifying predictive biomarkers for inhibitors of programmed cell death protein 1 receptor (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). Given the links between the stool microbiota, anticancer immunosurveillance, and general health, the composition of the gut microbiome has recently undergone investigation as a biomarker for immunotherapy. In this review, we highlight published results from preclinical and clinical studies to date supporting a relationship between the gut microbiome and antitumor efficacy of immune checkpoint inhibitors. Despite the promising and hypothesis-generating findings that have been produced in this arena to date, there remain some inconsistencies amongst present data that may need to be resolved to contribute to further development. Among these, a better understanding of the immunomodulatory function of the microbiome, standardization in sampling, sequencing techniques, and data analysis, and ensuring uniformity across various aspects of study design are warranted in conducting future prospective studies seeking to validate the gut microbiome as a potential biomarker of response to checkpoint blockade.
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Founding 16S responder cohort analysis · observational study
Why it is here: Associates gut bacterial profiles with ICI response in Japanese patients with advanced NSCLC.
Abstract · conclusions of the full text read too
BACKGROUND: Cancer immunotherapy is being developed as a promising alternative for advanced non-small cell lung cancer (NSCLC). However, novel biomarkers are required to select patients that will benefit from treatment with immune checkpoint inhibitors (ICIs) for a long period of time. The gut microbiome is expected to be a promising biomarker of ICI response owing to the regulation of the immune status within the host. METHODS: In this retrospective study, we included 17 Japanese patients with advanced NSCLC who were treated with ICIs for >3 months in our hospital. Fecal samples obtained from the patients during ICI treatment were analyzed by 16S ribosomal RNA gene sequencing. We examined the correlation between the diversity of the gut microbiome and treatment with ICIs. RESULTS: Several bacterial species were more abundant in ICI responders than in non-responders. Patients with abundant Lactobacillus and Clostridium tended to have a longer time to treatment failure (TTF) after receiving ICI than those with a lower abundance. CONCLUSIONS: In conclusion, the composition of the gut microbiome is associated with better clinical benefits from ICI treatment in Japanese patients with NSCLC. A further large-scale study is warranted to validate the composition of the gut microbiome as a novel clinical factor influencing the response to ICIs for an extended time in NSCLC.
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Founding prospective SCFA biomarker study · observational study
Why it is here: Measures fecal and plasma short-chain fatty acids in patients receiving PD-1 inhibitors.
Abstract · conclusions of the full text read too
Importance: Immunotherapy using immune checkpoint inhibitors has been remarkably effective for treating multiple cancer types, and the gut microbiome is a possible factor affecting immune checkpoint inhibitor efficacy. However, the association between the gut microbiome and immune status of the tumor microenvironment remains unclear. Short-chain fatty acids (SCFAs) are major end product metabolites produced by the gut microbiota and have wide-ranging impacts on host physiology. Objective: To evaluate fecal and plasma SCFAs in patients with solid cancer tumors treated with programmed cell death-1 inhibitors (PD-1i). Design, Setting, and Participants: This was a prospective cohort biomarker study of patients with cancer who planned therapy with PD-1i at Kyoto University Hospital between July 2016 and February 2019. Data were analyzed from October 2019 to February 2020. Exposures: Patients who were treated with nivolumab or pembrolizumab were classified into 2 groups based on their treatment response using Response Evaluation Criteria in Solid Tumors version 1.1: responders who achieved an objective response and nonresponders. Dietary information in terms of intake frequency was obtained. Concentrations of SCFAs in fecal and plasma samples collected before PD-1i administration were measured using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry. Main Outcomes and Measures: The concentration of SCFAs and progression-free survival. Results: Among 52 patients enrolled, the median (range) patient age was 67 (27-84) years, and 23 (44%) were women. Median (range) duration of follow-up of the survivors after administration of PD-1i was 2.0 (0.4-4.1) years. The overall response rate was 28.8%. High concentrations of some SCFAs were associated with longer progression-free survival. These included fecal acetic acid (hazard ratio [HR], 0.29; 95% CI, 0.15-0.54), propionic acid (HR, 0.08; 95% CI, 0.03-0.20), butyric acid (HR, 0.31; 95% CI, 0.16-0.60), valeric acid (HR, 0.53; 95% CI, 0.29-0.98), and plasma isovaleric acid (HR, 0.38; 95% CI, 0.14-0.99). Conclusions and Relevance: Results of this study suggest that fecal SCFA concentrations may associated with PD-1i efficacy; thus, SCFAs may be the link between the gut microbiota and PD-1i efficacy. Because fecal examinations are completely noninvasive, they may be applicable for routine monitoring of patients.
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[10] Gut Microbiome as a Potential Factor for Modulating Resistance to Cancer Immunotherapy
Founding Review Resistance mechanisms review · review
Why it is here: Examines how gut microbiota may influence resistance to checkpoint-targeted cancer immunotherapy.
Abstract · conclusions of the full text read too
Gut microbiota refers to the diverse community of more than 100 trillion microorganisms residing in our intestines. It is now known that any shift in the composition of gut microbiota from that present during the healthy state in an individual is associated with predisposition to multiple pathological conditions, such as diabetes, autoimmunity, and even cancer. Currently, therapies targeting programmed cell death protein 1/programmed cell death 1 ligand 1 or cytotoxic T-lymphocyte antigen-4 are the focus of cancer immunotherapy and are widely applied in clinical treatment of various tumors. Owing to relatively low overall response rate, however, it has been an ongoing research endeavor to identify the mechanisms or factors for improving the therapeutic efficacy of these immunotherapies. Other than causing mutations that affect gene expression, some gut bacteria may also activate or repress the host's response to immune checkpoint inhibitors. In this review, we have described recent advancements made in understanding the regulatory relationship between gut microbiome and cancer immunotherapy. We have also summarized the potential molecular mechanisms behind this interaction, which can serve as a basis for utilizing different kinds of gut bacteria as promising tools for reversing immunotherapy resistance in cancer.
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Founding Confounder-adjusted melanoma metagenomics · observational study
Why it is here: Profiles pretreatment stool in melanoma patients and tests taxa and pathways associated with inhibitor response while adjusting for confounders.
Abstract · conclusions of the full text read too
In patients with metastatic cancer, gut microbiome composition differs between responder and non-responders to immune checkpoint inhibitors. However, there is little consensus on the microbiome taxa associated with response or lack of response. Additionally, recognized confounders of gut microbiome composition have generally not been taken into account. In this study, metagenomic shotgun sequencing was performed on freshly frozen pre-treatment stool samples from 25 patients (12 responders and 13 non-responders) with unresectable metastatic melanoma treated with immune checkpoint inhibitors. We observed no significant differences in alpha-diversity and bacterial prevalence between responders and non-responders (P > 0.05). In a zero-inflated multivariate analysis, correcting for important confounders such as age, BMI and use of antibiotics, 68 taxa showed differential abundance between responders and non-responders (false-discovery rate < 0.05). Cox-regression analysis showed longer overall survival for carriers of Streptococcus parasanguinis [hazard ratio (HR): 6.9] and longer progression-free survival for carriers of Bacteroides massiliensis (HR: 3.79). In contrast, carriership of Peptostreptococcaceae (unclassified species) was associated with shorter overall survival (HR 0.18) and progression-free survival (HR 0.11). Finally, 17 microbial pathways differentially abundant between responder and non-responders were observed. These results underline the association between gut microbiome composition and response to immune checkpoint inhibitor therapy in a cohort of patients with cutaneous melanoma.
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Founding Review Melanoma metagenomic meta-analysis · observational study
Why it is here: Combines published patient cohorts to identify microbial taxa and functions associated with inhibitor response.
Abstract · conclusions of the full text read too
BACKGROUNDIdentifying factors conferring responses to therapy in cancer is critical to select the best treatment for patients. For immune checkpoint inhibition (ICI) therapy, mounting evidence suggests that the gut microbiome can determine patient treatment outcomes. However, the extent to which gut microbial features are applicable across different patient cohorts has not been extensively explored.METHODSWe performed a meta-analysis of 4 published shotgun metagenomic studies (Ntot = 130 patients) investigating differential microbiome composition and imputed metabolic function between responders and nonresponders to ICI.RESULTSOur analysis identified both known microbial features enriched in responders, such as Faecalibacterium as the prevailing taxa, as well as additional features, including overrepresentation of Barnesiella intestinihominis and the components of vitamin B metabolism. A classifier designed to predict responders based on these features identified responders in an independent cohort of 27 patients with the area under the receiver operating characteristic curve of 0.625 (95% CI: 0.348-0.899) and was predictive of prognosis (HR = 0.35, P = 0.081).CONCLUSIONThese results suggest the existence of a fecal microbiome signature inherent across responders that may be exploited for diagnostic or therapeutic purposes.FUNDINGThis work was funded by the Knut and Alice Wallenberg Foundation, BioGaia AB, and Cancerfonden.
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Founding Clinical gastrointestinal cancer cohort · observational study
Why it is here: Studies fecal microbiomes before and during treatment in gastrointestinal cancer patients receiving anti-PD-1/PD-L1 therapy.
Abstract
Abstract We report on a comprehensive analysis of the gut microbiomes of patients with gastrointestinal (GI) cancer receiving anti–PD-1/PD-L1 treatment. The human gut microbiota has been associated with clinical responses to anti–PD-1/PD-L1 immunotherapy in melanoma, non–small cell lung cancer, and renal cell carcinoma. We aimed to investigate this association in GI cancers. We also identified bacterial taxa with patient stratification potential. We recruited 74 patients with advanced-stage GI cancer receiving anti–PD-1/PD-L1 treatment and collected their fecal samples prior to and during immunotherapy, along with clinical evaluations. Our 16S rRNA taxonomy survey on the fecal samples revealed an elevation of the Prevotella/Bacteroides ratio in patients, with a preferred response to anti–PD-1/PD-L1 treatment, and a particular subgroup of responders harboring a significantly higher abundance of Prevotella, Ruminococcaceae, and Lachnospiraceae. The shotgun metagenomes of the same samples showed that patients exhibiting different responses had differential abundance of pathways related to nucleoside and nucleotide biosynthesis, lipid biosynthesis, sugar metabolism, and fermentation to short-chain fatty acids (SCFA). Gut bacteria that were capable of SCFA production, including Eubacterium, Lactobacillus, and Streptococcus, were positively associated with anti–PD-1/PD-L1 response across different GI cancer types. We further demonstrated that the identified bacterial taxa were predictive of patient stratification in both our cohort and melanoma patients from two previously published studies. Our results thus highlight the impact of gut microbiomes on anti–PD-1/PD-L1 outcomes, at least in a subset of patients with GI cancer, and suggest the potential of the microbiome as a marker for immune-checkpoint blockade responses. See articles by Tomita et al., p. 1236, and Hakozaki et al., p. 1243
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[14] Gut Microbiota and Antitumor Immunity: Potential Mechanisms for Clinical Effect
Review Mechanistic and intervention synthesis · review
Why it is here: Reviews intervention evidence and proposed immune mechanisms linking microbiota modulation to antitumor responses.
Abstract
Abstract Several landmark preclinical studies have shown an association between the gut microbiota and the effectiveness of immunotherapy for cancer. These studies have sparked clinical trials aimed at modulating the gut microbiota in order to improve clinical response rates to immunotherapy. Despite this, the mechanisms through which the gut microbiota influences the effectiveness of immunotherapy are still incompletely characterized. Preclinical and preliminary clinical findings from numerous types of gut microbiota modulation studies, including fecal transplantation, probiotics, consortia, and diet, demonstrate that favorable microbiota modulation is associated with increased intratumoral infiltration of CD8+ effector T cells. This CD8+ T-cell infiltration is often associated with enhanced intratumoral activity of T-helper type 1 cells and dendritic cells and a lower density of immunosuppressive cells. Herein, we discuss how gut microbiota may affect the activity of immune cells by at least three interlacing mechanisms: activation of pattern recognition receptors, molecular mimicry, and impact of metabolites. We also discuss the therapeutic potential and limitations of the different gut microbiota modulation techniques and their putative mechanisms of immune activation.
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Founding longitudinal metagenomic clinical study · observational study
Why it is here: Assesses microbiome composition and changes in relation to anti-PD-1 outcomes in hepatobiliary cancers.
Abstract · conclusions of the full text read too
BACKGROUND: The gut microbiome is associated with the response to immunotherapy for different cancers. However, the impact of the gut microbiome on hepatobiliary cancers receiving immunotherapy remains unknown. This study aims to investigate the relationship between the gut microbiome and the clinical response to anti-programmed cell death protein 1 (PD-1) immunotherapy in patients with advanced hepatobiliary cancers. METHODS: Patients with unresectable hepatocellular carcinoma or advanced biliary tract cancers who have progressed from first-line chemotherapy (gemcitabine plus cisplatin) were enrolled. Fresh stool samples were collected before and during anti-PD-1 treatment and analyzed with metagenomic sequencing. Significantly differentially enriched taxa and prognosis associated taxa were identified. The Kyoto Encyclopedia of Genes and Genomes database and MetaCyc database were further applied to annotate the differentially enriched taxa to explore the potential mechanism of the gut microbiome influencing cancer immunotherapy. RESULTS: In total, 65 patients with advanced hepatobiliary cancers receiving anti-PD-1 treatment were included in this study. Seventy-four taxa were significantly enriched in the clinical benefit response (CBR) group and 40 taxa were significantly enriched in the non-clinical benefit (NCB) group. Among these taxa, patients with higher abundance of Lachnospiraceae bacterium-GAM79 and Alistipes sp Marseille-P5997, which were significantly enriched in the CBR group, achieved longer progression-free survival (PFS) and overall survival (OS) than patients with lower abundance. Higher abundance of Ruminococcus calidus and Erysipelotichaceae bacterium-GAM147 enriched in the CBR group was also observed in patients with better PFS. In contrast, worse PFS and OS were found in patients with higher abundance of Veillonellaceae, which was significantly enriched in the NCB group. Functional annotation indicated that the taxa enriched in the CBR group were associated with energy metabolism while the taxa enriched in the NCB group were associated with amino acid metabolism, which may modulate the clinical response to immunotherapy in hepatobiliary cancers. In addition, immunotherapy-related adverse events were affected by the gut microbiome diversity and relative abundance. CONCLUSIONS: We demonstrate that the gut microbiome is associated with the clinical response to anti-PD-1 immunotherapy in patients with hepatobiliary cancers. Taxonomic signat
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Review Metabolite and clinical evidence review · review
Why it is here: Reviews microbial metabolites, antibiotic exposure, transplantation, and toxicity in checkpoint blockade.
Abstract · conclusions of the full text read too
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune inhibitory pathways. Administration of ICIs augments T cell-mediated immune responses against tumor, resulting in improved overall survival in cancer patients. It has emerged that the intestinal microbiome can modulate responses to ICIs via the host immune system and that the use of antibiotics can lead to reduced efficacy of ICIs. Recently, reports that fecal microbiota transplantation can lead to ICI therapy responses in patients previously refractory to therapy suggest that targeting the microbiome may be a viable strategy to reprogram the tumor microenvironment and augment ICI therapy. Intestinal microbial metabolites may also be linked to response rates to ICIs. In addition to response rates, certain toxicities that can arise during ICI therapy have also been found to be associated with the intestinal microbiome, including in particular colitis. A key mechanistic question is how certain microbes can enhance anti-tumor responses or, alternatively, predispose to ICI-associated colitis. Evidence has emerged that the intestinal microbiome can modulate outcomes to ICI therapies via two major mechanisms, including those that are antigen-specific and those that are antigen-independent. Antigen-specific mechanisms occur when epitopes are shared between microbial and tumor antigens that could enhance, or, alternatively, reduce anti-tumor immune responses via cross-reactive adaptive immune cells. Antigen-independent mechanisms include modulation of responses to ICIs by engaging innate and/or adaptive immune cells. To establish microbiome-based biomarkers of outcomes and specifically modulate the intestinal microbiome to enhance efficacy of ICIs in cancer immunotherapy, further prospective interventional studies will be required.
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Review Clinical studies literature review · review
Why it is here: Synthesizes clinical studies of microbiome profiles and immunotherapy outcomes across cancer types.
Abstract · conclusions of the full text read too
Background: Emerging evidence suggests that gut microbiota influences the clinical response to immunotherapy. This review of clinical studies examines the relationship between gut microbiota and immunotherapy outcomes. Method: A literature search was conducted in electronic databases Medline, PubMed and ScienceDirect, with searches for “cancer” and “immunotherapy/immune checkpoint inhibitor” and “microbiome/microbiota” and/or “fecal microbiome transplant FMT”. The relevant literature was selected for this article. Results: Ten studies examined patients diagnosed with advanced metastatic melanoma (n = 6), hepatocellular carcinoma (HCC) (n = 2), non-small cell lung carcinoma (NSCLC) (n = 1) and one study examined combination both NSCLC and renal cell carcinoma (RCC) (n = 1). These studies consistently reported that the gut microbiome profile prior to administering immune checkpoint inhibitors (ICIs) was related to clinical response as measured by progression-free survival (PFS) and overall survival (OS). Two studies reported that a low abundance of Bacteroidetes was associated with colitis. Two studies showed that patients with anti-PD-1 refractory metastatic melanoma experienced improved response rates and no added toxicity when receiving fecal microbiota transplant (FMT) from patients with anti-PD-1 responsive disease. Conclusions: Overall, significant differences in the diversity and composition of the gut microbiome were identified in ICIs responders and non-responders. Our findings provide new insights into the value of assessing the gut microbiome in immunotherapy. Further robust randomized controlled trials (RCTs) examining the modulatory effects of the gut microbiome and FMT on ICIs in patients not responding to immunotherapy are warranted.
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[18] The role of gut microbiome in modulating response to immune checkpoint inhibitor therapy in cancer
Review Clinical and mechanistic review · review
Why it is here: Reviews microbiome associations with checkpoint inhibitor benefit and immune-related adverse events.
Abstract · conclusions of the full text read too
Abstract: Immunotherapy has led to a paradigm shift in the treatment of several cancers. There have been significant efforts to identify biomarkers that can predict response and toxicities related to immune checkpoint inhibitor (ICPI) therapy. Despite these advances, it has been challenging to tease out why a subset of patients benefit more than others or why certain patients experience immune-related adverse events (irAEs). Although the immune-modulating properties of the human gut bacterial ecosystem are yet to be fully elucidated, there has been growing interest in evaluating the role of the gut microbiome in shaping the therapeutic response to cancer immunotherapy. Considerable research efforts are currently directed to utilizing metagenomic and metabolic profiling of stool microbiota in patients on ICPI-based therapies. Dysbiosis or loss of microbial diversity has been associated with a poor treatment response to ICPIs and worse survival outcomes in cancer patients. Emerging data have shown that certain bacterial strains, such as Faecalibacterium that confer sensitivity to ICPI, also have a higher propensity to increase the risk of irAEs. Additionally, the microbiome can modulate the local immune response at the intestinal interface and influence the trafficking of bacterial peptide primed T-cells distally, influencing the toxicity patterns to ICPI. Antibiotic or diet induced alterations in composition of the microbiome can also indirectly alter the production of certain bacterial metabolites such as deoxycholate and short chain fatty acids that can influence the anti-tumor tolerogenesis. Gaining sufficient understanding of the exact mechanisms underpinning the interplay between ICPI induced anti-tumor immunity and the immune modulatory role gut microbiome can be vital in identifying potential avenues of improving outcomes to cancer immunotherapy. In the current review, we have summarized and highlighted the key emerging data supporting the role of gut microbiome in regulating response to ICPIs in cancer.
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Cross-cohort melanoma analysis · observational study
Why it is here: Tests microbiome-response associations across melanoma cohorts and assesses the reproducibility of predictive signatures.
Abstract
The composition of the gut microbiome has been associated with clinical responses to immune checkpoint inhibitor (ICI) treatment, but there is limited consensus on the specific microbiome characteristics linked to the clinical benefits of ICIs. We performed shotgun metagenomic sequencing of stool samples collected before ICI initiation from five observational cohorts recruiting ICI-naive patients with advanced cutaneous melanoma (n = 165). Integrating the dataset with 147 metagenomic samples from previously published studies, we found that the gut microbiome has a relevant, but cohort-dependent, association with the response to ICIs. A machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts. Accordingly, a panel of species, including Bifidobacterium pseudocatenulatum, Roseburia spp. and Akkermansia muciniphila, associated with responders was identified, but no single species could be regarded as a fully consistent biomarker across studies. Overall, the role of the human gut microbiome in ICI response appears more complex than previously thought, extending beyond differing microbial species simply present or absent in responders and nonresponders. Future studies should adopt larger sample sizes and take into account the complex interplay of clinical factors with the gut microbiome over the treatment course.
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[20] Gut microbiome in modulating immune checkpoint inhibitors
Review Mechanistic evidence review · review
Why it is here: Reviews how gut microbiome variation may shape checkpoint inhibitor responses and how microbiota can be modified.
Abstract · conclusions of the full text read too
Gut microbiome has been increasingly recognized for its influence on a diverse array of human diseases including cancer, and may also influence the outcome of cancer therapies. A prime example is seen in immunotherapy, for which gut microbes determine the therapeutic responses associated with immune checkpoint inhibitors (ICIs) in preclinical models and patient cohorts. This evidence hints that inter-individual variations in the gut microbiota may account for the significant heterogeneity in immunotherapeutic responses to ICIs. Understanding the functional role of gut microbiome in regulating not only mucosal but also systemic immunity and cancer is critical to move forward in this era of precision medicine. What's more, microbiota can be modified via several different strategies that are essential for the efforts in expanding immunotherapy efficacy. This review summarizes latest knowledge about the interactions between microbiome, host immunity and cancer, and strategies to modulate the microbiome with implications to be translated into clinic. FUNDING: This study was supported by National Key R&D Program of China (No. 2020YFA0509200/2020YFA0509203), RGC Theme-based Res Scheme Hong Kong (T21-705/20-N).
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[21] Gut microbiota influence immunotherapy responses: mechanisms and therapeutic strategies
Review Mechanisms and therapeutic strategies review · review
Why it is here: Reviews microbial effects on antitumor immunity and metabolites as potential means to improve immunotherapy.
Abstract · conclusions of the full text read too
The gut microbiota have long been recognized to play a key role in human health and disease. Currently, several lines of evidence from preclinical to clinical research have gradually established that the gut microbiota can modulate antitumor immunity and affect the efficacy of cancer immunotherapies, especially immune checkpoint inhibitors (ICIs). Deciphering the underlying mechanisms reveals that the gut microbiota reprogram the immunity of the tumor microenvironment (TME) by engaging innate and/or adaptive immune cells. Notably, one of the primary modes by which the gut microbiota modulate antitumor immunity is by means of metabolites, which are small molecules that could spread from their initial location of the gut and impact local and systemic antitumor immune response to promote ICI efficiency. Mechanistic exploration provides novel insights for developing rational microbiota-based therapeutic strategies by manipulating gut microbiota, such as fecal microbiota transplantation (FMT), probiotics, engineered microbiomes, and specific microbial metabolites, to augment the efficacy of ICI and advance the age utilization of microbiota precision medicine.
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Review melanoma cohort meta-analysis · observational study
Why it is here: Associates microbial signatures with anti-PD-1 outcomes and immune-related adverse events.
Abstract
Ample evidence indicates that the gut microbiome is a tumor-extrinsic factor associated with antitumor response to anti-programmed cell death protein-1 (PD-1) therapy, but inconsistencies exist between published microbial signatures associated with clinical outcomes. To resolve this, we evaluated a new melanoma cohort, along with four published datasets. Time-to-event analysis showed that baseline microbiota composition was optimally associated with clinical outcome at approximately 1 year after initiation of treatment. Meta-analysis and other bioinformatic analyses of the combined data show that bacteria associated with favorable response are confined within the Actinobacteria phylum and the Lachnospiraceae/Ruminococcaceae families of Firmicutes. Conversely, Gram-negative bacteria were associated with an inflammatory host intestinal gene signature, increased blood neutrophil-to-lymphocyte ratio, and unfavorable outcome. Two microbial signatures, enriched for Lachnospiraceae spp. and Streptococcaceae spp., were associated with favorable and unfavorable clinical response, respectively, and with distinct immune-related adverse effects. Despite between-cohort heterogeneity, optimized all-minus-one supervised learning algorithms trained on batch-corrected microbiome data consistently predicted outcomes to programmed cell death protein-1 therapy in all cohorts. Gut microbial communities (microbiotypes) with nonuniform geographical distribution were associated with favorable and unfavorable outcomes, contributing to discrepancies between cohorts. Our findings shed new light on the complex interaction between the gut microbiome and response to cancer immunotherapy, providing a roadmap for future studies. Integrated analysis of microbiome and host cell transcriptional data on clinically annotated cohorts of patients with melanoma who were treated with anti-programmed cell death protein-1, uncovers new associations of streptococcus species with immune-related adverse effects and finds consistent microbiome associations with clinical outcomes.
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[23] Gut microbiome homeostasis and the future of probiotics in cancer immunotherapy
Review review of microbiome interventions · review
Why it is here: Examines probiotics, diet, and transplantation as potential ways to affect immunotherapy outcomes.
Abstract · conclusions of the full text read too
The gut microbiome has an impact on cancer immune surveillance and immunotherapy, with recent studies showing categorical differences between immunotherapy-sensitive and immunotherapy-resistant cancer patient cohorts. Although probiotics are traditionally being supplemented to promote treatments or sustain therapeutic benefits; the FDA has not approved any for use with immunotherapy. The first step in developing probiotics for immunotherapy is identifying helpful or harmful bacteria down to the strain level. The gut microbiome's heterogeneity before and during treatment is also being investigated to determine microbial strains that are important for immunotherapy. Moreover, Dietary fiber intake, prebiotic supplementation and fecal microbiota transplantation (FMT) were found to enhance intratumoral CD8+ T cell to T-reg ratio in the clinics. The possibility of probiotic immunotherapy as a "living adjuvant" to CAR treatment and checkpoint blockade resistance is actively being investigated.
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[24] The Role of the Gut Microbiome in Cancer Immunotherapy: Current Knowledge and Future Directions
Review Current evidence and directions review · review
Why it is here: Reviews microbial signatures associated with checkpoint inhibitor response, resistance, and adverse events.
Abstract · conclusions of the full text read too
Cancer immunotherapy is a treatment modality that aims to stimulate the anti-tumor immunity of the host to elicit favorable clinical outcomes. Immune checkpoint inhibitors (ICIs) gained traction due to the lasting effects and better tolerance in patients carrying solid tumors in comparison to conventional treatment. However, a significant portion of patients may present primary or acquired resistance (non-responders), and thus, they may have limited therapeutic outcomes. Resistance to ICIs can be derived from host-related, tumor-intrinsic, or environmental factors. Recent studies suggest a correlation of gut microbiota with resistance and response to immunotherapy as well as with the incidence of adverse events. Currently, preclinical and clinical studies aim to elucidate the unique microbial signatures related to ICI response and anti-tumor immunity, employing metagenomics and/or multi-omics. Decoding this complex relationship can provide the basis for manipulating the malleable structure of the gut microbiota to enhance therapeutic success. Here, we delve into the factors affecting resistance to ICIs, focusing on the intricate gut microbiome-immunity interplay. Additionally, we review clinical studies and discuss future trends and directions in this promising field.
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[25] A gut microbial signature for combination immune checkpoint blockade across cancer types
Recent Review strain-resolved metagenomic cohort analysis · observational study
Why it is here: Tests whether strain-level microbiome profiles predict response to combination checkpoint blockade across cancers.
Abstract
Immune checkpoint blockade (ICB) targeting programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte protein 4 (CTLA-4) can induce remarkable, yet unpredictable, responses across a variety of cancers. Studies suggest that there is a relationship between a cancer patient's gut microbiota composition and clinical response to ICB; however, defining microbiome-based biomarkers that generalize across cohorts has been challenging. This may relate to previous efforts quantifying microbiota to species (or higher taxonomic rank) abundances, whereas microbial functions are often strain specific. Here, we performed deep shotgun metagenomic sequencing of baseline fecal samples from a unique, richly annotated phase 2 trial cohort of patients with diverse rare cancers treated with combination ICB (n = 106 discovery cohort). We demonstrate that strain-resolved microbial abundances improve machine learning predictions of ICB response and 12-month progression-free survival relative to models built using species-rank quantifications or comprehensive pretreatment clinical factors. Through a meta-analysis of gut metagenomes from a further six comparable studies (n = 364 validation cohort), we found cross-cancer (and cross-country) validity of strain-response signatures, but only when the training and test cohorts used concordant ICB regimens (anti-PD-1 monotherapy or combination anti-PD-1 plus anti-CTLA-4). This suggests that future development of gut microbiome diagnostics or therapeutics should be tailored according to ICB treatment regimen rather than according to cancer type.
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[26] Critical role of the gut microbiota in immune responses and cancer immunotherapy
Recent Review Mechanisms and interventions review · review
Why it is here: Reviews microbiome mechanisms, adverse events, and strategies for improving cancer immunotherapy efficacy.
Abstract
The gut microbiota plays a critical role in the progression of human diseases, especially cancer. In recent decades, there has been accumulating evidence of the connections between the gut microbiota and cancer immunotherapy. Therefore, understanding the functional role of the gut microbiota in regulating immune responses to cancer immunotherapy is crucial for developing precision medicine. In this review, we extract insights from state-of-the-art research to decipher the complicated crosstalk among the gut microbiota, the systemic immune system, and immunotherapy in the context of cancer. Additionally, as the gut microbiota can account for immune-related adverse events, we discuss potential interventions to minimize these adverse effects and discuss the clinical application of five microbiota-targeted strategies that precisely increase the efficacy of cancer immunotherapy. Finally, as the gut microbiota holds promising potential as a target for precision cancer immunotherapeutics, we summarize current challenges and provide a general outlook on future directions in this field.
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[27] Gut microbiota reshapes cancer immunotherapy efficacy: Mechanisms and therapeutic strategies
Recent Review Mechanisms and strategies review · review
Why it is here: Examines microbial composition and metabolites in relation to immunotherapy responses and adverse events.
Abstract · conclusions of the full text read too
Gut microbiota is essential for maintaining local and systemic immune homeostasis in the presence of bacterial challenges. It has been demonstrated that microbiota play contrasting roles in cancer development as well as anticancer immunity. Cancer immunotherapy, a novel anticancer therapy that relies on the stimulation of host immunity, has suffered from a low responding rate and incidence of severe immune-related adverse events (irAEs). Previous studies have demonstrated that the diversity and composition of gut microbiota were associated with the heterogeneity of therapeutic effects. Therefore, alteration in microbiota taxa can lead to improved clinical outcomes in immunotherapy. In this review, we determine whether microbiota composition or microbiota-derived metabolites are linked to responses to immunotherapy and irAEs. Moreover, we discuss various approaches to improve immunotherapy efficacy or reduce toxicities by modulating microbiota composition.
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Recent Review Solid tumor evidence review · review
Why it is here: Reviews microbiome associations with checkpoint inhibitor efficacy and toxicity and potential interventions in solid tumors.
Abstract · conclusions of the full text read too
Immunotherapy with immune checkpoint inhibitors represents a revolutionary approach to the treatment of solid tumors, including malignant melanoma, lung cancer, and gastrointestinal malignancies. Anti-CTLA-4 and anti-PD-1/PDL-1 therapies provide prolonged survival for cancer patients, but their efficacy and safety are highly variable. This review focuses on the crucial role of the gut microbiome in modulating the efficacy and toxicity of immune checkpoint blockade. Studies suggest that the composition of the gut microbiome may influence the response to immunotherapy, with specific bacterial strains able to promote an anti-tumor immune response. On the other hand, dysbiosis may increase the risk of adverse effects, such as immune-mediated colitis. Interventions aimed at modulating the microbiome, including the use of probiotics, prebiotics, fecal microbial transplantation, or dietary modifications, represent promising strategies to increase treatment efficacy and reduce toxicity. The combination of immunotherapy with the microbiome-based strategy opens up new possibilities for personalized treatment. In addition, factors such as physical activity and nutritional supplementation may indirectly influence the gut ecosystem and consequently improve treatment outcomes in refractory patients, leading to enhanced patient responses and prolonged survival.
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[29] Longitudinal gut microbiome changes in immune checkpoint blockade-treated advanced melanoma
Recent longitudinal melanoma microbiome profiling · observational study
Why it is here: Tracks microbiome changes during checkpoint blockade and compares patterns by progression-free survival.
Abstract
Abstract Multiple clinical trials targeting the gut microbiome are being conducted to optimize treatment outcomes for immune checkpoint blockade (ICB). To improve the success of these interventions, understanding gut microbiome changes during ICB is urgently needed. Here through longitudinal microbiome profiling of 175 patients treated with ICB for advanced melanoma, we show that several microbial species-level genome bins (SGBs) and pathways exhibit distinct patterns from baseline in patients achieving progression-free survival (PFS) of 12 months or longer (PFS ≥12) versus patients with PFS shorter than 12 months (PFS <12). Out of 99 SGBs that could discriminate between these two groups, 20 were differentially abundant only at baseline, while 42 were differentially abundant only after treatment initiation. We identify five and four SGBs that had consistently higher abundances in patients with PFS ≥12 and <12 months, respectively. Constructing a log ratio of these SGBs, we find an association with overall survival. Finally, we find different microbial dynamics in different clinical contexts including the type of ICB regimen, development of immune-related adverse events and concomitant medication use. Insights into the longitudinal dynamics of the gut microbiome in association with host factors and treatment regimens will be critical for guiding rational microbiome-targeted therapies aimed at enhancing ICB efficacy.
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[30] Modulating gut microbiome in cancer immunotherapy: Harnessing microbes to enhance treatment efficacy
Recent Review review of microbiome-targeted strategies · review
Why it is here: Reviews microbiome and metabolite mechanisms alongside interventions intended to improve immunotherapy.
Abstract
Immunotherapy has emerged as a robust approach against cancer, yet its efficacy has varied among individuals, accompanied by the occurrence of immune-related adverse events. As a result, the efficacy of immunotherapy is far from satisfactory, and enormous efforts have been invested to develop strategies to improve patient outcomes. The gut microbiome is now well acknowledged for its critical role in immunotherapy, with better understanding on host-microbes interaction in the context of cancer treatment. Also, an increasing number of trials have been conducted to evaluate the potential and feasibility of microbiome-targeting approaches to enhance efficacy of cancer treatment in patients. Here, the role of the gut microbiome and metabolites (e.g., short-chain fatty acids, tryptophan metabolites) in immunotherapy and the underlying mechanisms are explored. The application of microbiome-targeting approaches that aim to improve immunotherapy efficacy (e.g., fecal microbiota transplantation, probiotics, dietary intervention) is also elaborated, with further discussion on current challenges and suggestions for future research.