Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients

High diversity of gut microbiome favored clinical outcomes of anti-PD-1 immunotherapy in melanoma patients in the Western population.

“Recently, Gopalakrishnan et al. 35 reported that patients with a high diversity of gut microbiome favored the clinical outcomes of anti-PD-1 immunotherapy in melanoma patients in the Western population.”

Previous studies report an association of gram-negative bacteria such as Akkermansia muciniphila, Alistipes, and Porphyromonas with better clinical response to immunotherapy.

“There are several previous studies reporting the association of gram-negative bacteria, such as Akkermansia muciniphila, Alistipes, and Porphyromonas with better clinical response to immunotherapy.14,15,36”

Two additional studies identified an association of the commensal microbiome with anti-PD-1 mAb efficacy in different solid cancers.

“Two additional studies have identified an association of the commensal microbiome with anti–PD-1 mAb efficacy in different solid cancers (7,14).”

The gut microbiome can modulate tumor response to immunotherapy.

“The gut microbiome can modulate tumor response to immunotherapy, but its effect on HCC remains unclear.”

Patients with melanoma who were responders to anti-PD-1 immunotherapy had a higher alpha diversity of fecal microbiota and higher relative abundance of Ruminococcaceae than non-responders.

“A human study demonstrated that patients with melanoma who were responders to anti-PD-1 immunotherapy had a higher alpha diversity of fecal microbiota and higher relative abundance of Ruminococcaceae than non-responders.11”

Antitumor immunity was enhanced in germ-free mice receiving fecal transfer from responding patients.

“antitumor immunity was enhanced in germ-free mice receiving fecal transfer from the responding patients [9, 10].”

In human melanoma patients undergoing immunotherapy, gut microbiome composition has been significantly associated with clinical response.

“In human melanoma patients undergoing immunotherapy, gut microbiome composition has been significantly associated with clinical response [9–12]”

Gut microbiota composition and diversity are predictive of response to ICI immunotherapy.

“The three studies all demonstrated that gut microbiota composition and diversity were predictive of response to ICI immunotherapy [31–33].”

FMT from ICI responding patients to germ-free or antibiotic-treated mice improves tumor control and ameliorates responses to ICI, whereas FMT from non-responders fails to do so.

“A similar finding was that fecal microbiota transplantation (FMT) from ICI responding patients to germ-free or antibiotic-treated mice could improve tumor control and ameliorate responses to ICI, whereas FMT from non-responders failed to do so [31–33].”

Several studies have indicated that FMT could augment the antitumor effect of ICI and overcome resistance to immunotherapy.

“Recently, several studies have indicated that FMT could augment the antitumor effect of ICI and overcome resistance to immunotherapy [31–33].”

Specific gut microbes, such as Bifidobacterium, Akkermansia, Enterococcus, Faecalibacterium, and Ruminococcaceae, play the role of immune adjuvants in ICI immunotherapy.

“Moreover, specific gut microbes, such as Bifidobacterium [16, 33, 51, 141], Akkermansia [31, 38], Enterococcus [15, 33, 141], Faecalibacterium [49, 142], and Ruminococcaceae [32], play the role of immune adjuvants in ICI immunotherapy.”

Intestinal dysbiosis, broadly defined as an imbalance in the composition or function of the gut microbiota, is a significant contributor to resistance against immune checkpoint inhibitor (ICI) therapies.

“Intestinal dysbiosis, broadly defined as an imbalance in the composition or function of the gut microbiota, is a significant contributor to resistance against immune checkpoint inhibitor (ICI) therapies.1–16,”

α-diversity at baseline has been associated with favorable clinical outcomes in ICI therapies.

“Notably, α-diversity at baseline has been associated with favorable clinical outcomes in ICI therapies.5,147”

In preclinical models, the antitumor activity of immune checkpoint inhibitors requires gut microbial components.

“First, in pre-clinical models, experiments with germ-free or antibiotic (ATB)treated mice unraveled that the antitumor activity of ICI requires the presence of gut microbial components 19 .”

These transcriptomic results support the possibility that Akk could promote the elicitation or recirculation of Th1 cells into the tumor microenvironment, as previously shown in mouse models.

“These results support the possibility that Akk could promote the elicitation or recirculation of Th1 cells into the tumor microenvironment, as previously shown in mouse models 18,19 .”

For each individual study, a marked difference in beta-diversity between responders and nonresponders was observed only in the Gopalakrishnan et al. data set.

“For each individual study, we only observed a marked difference in beta-diversity between the R and NR groups in the Gopalakrishnan et al. data set (15) (Figure 2A).”

The gut microbiome influences the response to checkpoint inhibitors in patients with cancer.

“Previous studies have suggested that the gut microbiome influences the response to checkpoint inhibitors (CPIs) in patients with cancer.”

Melanoma patients with a more diverse intestinal microbiome are more likely to have a favorable response to immune checkpoint blockade and improved systemic and antitumor immunity.

“For example, melanoma patients are more likely to have a favorable response to immune checkpoint blockade and exhibit improved systemic and antitumor immunity if they have a more diverse intestinal microbiome11.”

Dysbiosis of the gut microbiome confers a predisposition to certain malignancies and influences the body's response to chemotherapy, radiotherapy, and immunotherapy.

“Studies have suggested that dysbiosis of the gut microbiome confers a predisposition to certain malignancies and influences the body’s response to a variety of cancer therapies, including chemotherapy, radiotherapy, and immunotherapy6,8–11.”

Multiple studies have linked a favorable gut microbiome to anti-PD-1 response in cancer patients, but its precise composition remains incompletely understood.

“Although multiple studies have reported that a favorable gut microbiome is associated with response to anti–PD-1 in cancer patients, its precise composition is not yet fully understood (10–12).”

In melanoma, certain bacterial species in Actinobacteria and Firmicutes are associated with favorable anti-PD-1 response, though studies show limited concordance.

“Specifically in melanoma, key bacterial species belonging to various phyla, including Actinobacteria (Bifidobacteriaceae spp. and Coriobacteriaceae spp.) and Firmicutes (Ruminococcaceae spp. and Lachnospiraceae spp.), are associated with favorable response to mAbs targeting PD-1 in cancer patients, although limited concordance among the identified species has been reported in different studies (10”

Gut bacterial commensals previously linked to increased anti-PD-1 response (F. prausnitzii and A. muciniphila) and decreased response (Bacteroides genus) were negatively and positively correlated with CXCL8, respectively.

“we observed that gut bacterial commensals that were previously shown to increase (F. prausnitzii and Akkermansia muciniphila) and decrease (Bacteroides genus) responses to anti–PD-1 (10) were negatively and positively correlated with CXCL8 (IL-8), respectively.”

In mice, giving certain gut commensals or FMT promotes anti-PD-1 efficacy in melanoma-bearing mice.

“administration of certain gut commensals or fecal microbiota transplantation (FMT) promotes anti–PD-1 efficacy in melanoma-bearing mice (10–12).”

In mice, the composition of the gut microbiome modulates the therapeutic activity of anti-PD-1 and anti-PD-L1.

“In mice, composition of the gut microbiome modulates therapeutic activity of anti–PD-1 and anti–programmed death-ligand 1 (PD-L1)”

The gut microbiota is associated with the efficacy of anti-CTLA4, anti-PD-1, and anti-PD-L1 treatment.

“Recently, the gut microbiota has emerged as a potent new factor associated with the efficacy of anti–CTLA4, anti–PD-1, and anti–PD-L1 treatment (8-14).”

Gut bacteria influence how cancer patients respond to immune checkpoint blockade.

“Gut bacteria modulate the response to immune checkpoint blockade (ICB) treatment in cancer”

Mouse models provide evidence that gut microbiota modifications from FMT improve ICI response, but magnitude depends on mouse strain or provider, sex, and experimental conditions.

“Studies in mouse models have provided compelling evidence that gut microbiota modifications resulting from faecal microbiota transplantation (FMT) improve ICI response rates38,42,91; however, the magnitude of these antitumour responses depends of factors such as the mouse strain or provider, mouse sex and individual experimental conditions106.”

Single studies in melanoma patients receiving ICIs identified enrichment of F. prausnitzii, Bifidobacterium longum, and Bacteroides caccae in responders, but concordance across studies was low.

“single studies in patients with melanoma receiving ICIs identified an enrichment of species such as F. prausnitzii, Bifidobacterium longum and Bacteroides caccae in samples from patients with a response (‘responders’)38,44,91, although the concordance of these microbiome characteristics with treatment response across studies was low97.”

Following epidemiological demonstration of negative effect of antibiotics on ICI efficacy, specific microbial taxa have been associated with response or resistance to ICIs across distinct cancer types.

“Over the past decade, following the epidemiological demonstration of the negative effect of antibiotics on the efficacy of ICIs13,42,90, specific microbial taxa have been associated with response or resistance to ICIs across distinct cancer types26,38–40,42,91–100.”

Meta-analysis and mega-analysis included 12 cohorts from eight studies across three cancer types, with 248 responders and 513 non-responders classified by RECIST1.1.

“we performed a meta-analysis and mega-analysis of stools taxonomically profiled with MetaPhlAn 4 (ref. 37) and from patients enrolled in 12 cohorts from eight published studies26,38–44 across three cancer types, and classified as responders (n = 248) or non-responders (n = 513) based on RECIST1.1 criteria response rates”

A meta-analysis of microbial sequencing from nine separate melanoma cohorts treated with αPD-1 found that greater pfl abundance was associated with ICI efficacy.

“Our meta-analysis of microbial sequencing data from nine independent αPD-1-treated melanoma cohorts82–88 revealed a higher abundance of pfl, a key enzyme in bacterial formate production, linked to ICI efficacy.”

The balance computed for patients from six independent melanoma cohorts achieved a comparable AUC in several independent cohorts despite small sample sizes and heterogeneity in DNA isolation protocols and sequencing platforms.

“We next tested the generalizability of the balance described in Fig. 2a by computing it for patients from six independent melanoma cohorts5,7–10,12. Despite small sample sizes and large heterogeneity in terms of DNA isolation protocols and sequencing platforms (Supplementary Table 6), this analysis showed that the balance achieves a comparable AUC in several of the independent cohorts (Extended”

Species linked to ICB outcomes show little agreement across studies.

“However, there is limited concordance among species identified across studies, which included small numbers of patients and used different analytical approaches, not always adjusted for multiple testing4,5,12,13.”

The gut microbiome functions as a tumor-extrinsic biomarker that predicts response to immune checkpoint blockade.

“The intestinal microbiome has emerged as a tumor-extrinsic predictive biomarker to immune checkpoint blockade (ICB)1–6.”

In mice, giving specific gut commensals improves the effectiveness of anti-PD-1 treatment.

“Administration of certain gut commensals promotes efficacy of anti-programmed cell death protein-1 (PD-1) therapy in mice, providing evidence that microbiota can drive immunotherapy outcomes4–6.”

These results confirm previous observations of biphasic effects for the Bacteroides genus dependent on the specific treatment agent(s) used.

“These results confirm previous observations of biphasic effects for the Bacteroides genus dependent on the specific treatment agent(s) used9,40,41.”

Distinct gut microbial genera and species are associated with CD8+ T cell infiltration and survival in melanoma patients.

“With regard to adaptive immunity, distinct gut microbial genera and species are associated with CD8+ T cell infiltration and survival in patients with melanoma.”

Across cancer indications and geographic sites, the taxonomic composition of gut and to some degree tumor microbiota correlates with ICI responses in melanoma and other cancers.

“First, correlations have been drawn across cancer indications and geographical sites between the taxonomic composition of the gut (and to some degree tumor) microbiota, and ICI responses in patients with melanoma and other cancers.”

Prior studies of melanoma, NSCLC, and RCC patients on checkpoint blockade implicated increased alpha-diversity and specific members of major bacterial phyla in clinical response.

“Several studies have examined the stool composition of patients on checkpoint blockade with melanoma, non-small cell lung cancer (NSCLC), and renal cell cancer (RCC) (5–10). These studies have implicated increased alpha-diversity (8), along with specific members of each of the major bacterial phyla colonizing humans”

Prior studies, small and methodologically variable, suggest the gut microbiome may be a modifiable biomarker for ICI response, but the specific bacteria or communities implicated have been inconsistent across populations.

“Several studies, small in size and using variable analytical methods, suggest the gut microbiome may be a novel, modifiable biomarker for tumor response rates, but the specific bacteria or bacterial communities putatively impacting ICI responses have been inconsistent across the studied populations.”

Most of the original studies used nonparametric tests but did not correct for multiple hypothesis testing, except the Gopalakrishnan cohort.

“Overall, the majority of these studies used non-parametric testing but did not apply multiple hypothesis testing correction in the initial analysis, with the exception of the Gopalakrishnan cohort (8).”

The standardized 16S rRNA amplicon method produced relative abundance profiles comparable to metagenomic data, including for Faecalibacterium prausnitzii and Akkermansia muciniphila.

“These results indicate that data from our standardized methodology for 16S rRNA amplicon data produces comparable relative abundance profiles, including for high-interest species such as Faecalibacterium prausnitzii and Akkermansia muciniphila (Fig S1).”

The prior studies largely identified different microbes, and there is no consensus on which microbial signals associate with response or whether they are tumor-specific or affected by clinical metadata.

“While individually significant, a feature of these studies is that each has largely identified different sets of microbes and, overall, there is a lack of consensus regarding the microbial signals associated with clinical response and/or whether putative microbiota signals are tumor-specific or impacted by other clinical metadata.”

In prior studies, nonresponders' gut microbiota appeared less diverse, with Bacteroides, Ruminococcus, and Roseburia prominent.

“In contrast, the gut microbiota of non-responding patients seemed to be less diverse, with the genera Bacteroides (phylum Bacteroidetes), Ruminococci and Roseburia (both Firmicutes) being prominent.”

In the Gopalakrishnan cohort, higher alpha diversity (richness and evenness) correlated with tumor response to checkpoint inhibition.

“we confirmed that higher alpha diversity (richness and evenness) correlated with tumor response to checkpoint inhibition in the Gopalakrishan cohort (Fig. S2B) (8)”

In melanoma, greater diversity and relative abundance of fecal Ruminococcaceae have been linked to response to immune checkpoint inhibitors.

“Recent studies have shown that higher diversity and relative abundance of fecal Ruminococcaceae are associated with response to ICIs in patients with melanoma26.”

Prior studies found Akkermansia muciniphila associated with favorable clinical outcomes in melanoma, NSCLC, and renal cell carcinoma patients receiving immune checkpoint inhibitors.

“Similarly, Akkermansia muciniphila was associated with favorable clinical outcomes in patients with melanoma, NSCLC and renal cell carcinoma receiving ICIs in previous studies26,27.”

The gut microbiome has multiple effects on tumor biology, including transformation, progression, and response to anticancer therapies including immunotherapy.

“The gut microbiome has been shown to have multiple effects on tumor biology, such as the transformation process, tumor progression, and the response to anticancer therapies including immunotherapy (21-29).”

Several bacterial biomarkers have been reported for response to checkpoint inhibitors in non-GI cancer indications.

“For example, several bacterial biomarkers have been reported for response to checkpoint inhibitors in non-GI cancer indications (Frankel et al., 2017; Gopalakrishnan et al., 2018; Matson et al., 2018; Peters et al., 2019; Routy et al., 2018).”

Microbiota in the gut and in tumours can influence cancer patient survival and treatment response.

“as the gut and tumour microbiota can affect the survival of patients with cancer and their responses to therapy8,14,40–42,50”

In previous studies, a significantly higher relative abundance of Ruminococcaceae was identified in melanoma patients responding to anti-PD-1 immunotherapy.

“In previous studies, a significantly higher relative abundance of Ruminococcaceae was identified in melanoma patients responding to anti-PD-1 immunotherapy [7]”

Gopalakrishnan et al. found a statistically significant positive correlation between CD8+ T cell infiltrate in the tumor and the Faecalibacterium genus as well as the Ruminococcaceae family.

“Gopalakrishnan et al. compared the tumor-associated immune infiltrates via multi-parameter immunohistochemistry (IHC) and found a statistically significant positive correlation between CD8+ T cell infiltrate in the tumor and the Faecalibacterium genus as well as the Ruminococcaceae family”

The role of the gut microbiome in modulating tumor responses to immunotherapy in melanoma, non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma has received increased attention across a series of studies.

“The role of the gut microbiome in modulating tumor responses to immunotherapy in melanoma [5–7], non-small cell lung cancer, renal cell carcinoma, and urothelial carcinoma [6, 8] has received increased attention across a series of studies in recent years.”

Different reports have identified different microbial taxa as associated with ICB response in cancer patients.

“Microbial taxa associated with response to ICB in cancer patients differed among different reports (Gopalakrishnan et al., 2018; Matson et al., 2018; Routy et al., 2018).”

Analysis of 112 buccal and fecal samples from patients with metastatic melanoma showed that the response to anti-PD-1 therapy depends on differences in the diversity and composition of the patient gut microbiota of responders vs. non-responders.

“The analysis of 112 buccal and fecal samples from patients with metastatic melanoma also showed that the response to anti-PD-1 therapy depends on differences in the diversity and composition of the patient gut microbiota of responders vs. non-responders (179).”

These data demonstrated that, in responding patients, there was a relative abundance of bacteria of the Ruminococcaceae family.

“These data demonstrated that, in responding patients, there was a relative abundance of bacteria of the Ruminococcaceae family.”

Akkermansia muciniphila and Faecalibacterium correlate with better anti-PDCD1 efficacy, perhaps by drawing more T cells into tumors and enhancing their activity.

“A muciniphila195 and Faecalibacterium196 have been associated with greater efficacy of PDCD1 blocking agents—possibly by increasing recruitment of T cells to tumors and their functions there.”

Specific gut bacteria, including Bacteroides fragilis, Bacteroides thetaiotaomicron, Bifidobacterium, Akkermansia muciniphila and Faecalibacterium spp., have favourable responses to cancer immunotherapy in preclinical tumour models and patients with cancer.

“Such as Bacteroides fragilis, Bacteroides thetaiotaomicron, Bifidobacterium, Akkermansia muciniphila and Faecalibacterium spp. have been shown to have favourable responses to cancer immunotherapy in both preclinical tumour models and patients with cancer.12–15”

Presence of fecal A. muciniphila, Ruminococcaceae, and Faecalibacterium is linked to favorable outcome to anti-PD-1 treatment in humans.

“Studies in humans were further able to link the presence of fecal A. muciniphila, Ruminococcaceae, and Faecalibacterium to a favorable outcome to anti-PD-1 treatment (98, 126)”

Gut bacteria influence immune system activation, promote cancer-associated inflammation, and affect tumor responses to therapy.

“These studies suggest that gut bacteria influences the activation of the immune system, promoting cancer-associated inflammation and ultimately affecting tumor responses to therapies.”

The gut microbiota is a host factor that mediates tumor responses to chemotherapy and immunotherapy in melanoma and lung cancer.

“The key role of the gut microbiota as a host factor mediating tumor responses to chemotherapy and immunotherapy in patients with melanoma and lung cancers has been recently highlighted”

Recent studies demonstrated positive effects of immunotherapy on melanoma with FMT in an animal model and clinical trial.

“Furthermore, recent studies also demonstrated the positive effects of immunotherapy on melanoma with FMT in an animal model and clinical trial.45,46”

Responses to immune checkpoint therapies correlate with commensal gut flora, and responders and nonresponders appear to differ substantially in gut microbial diversity and composition.

“Responses to ICTs have been correlated with commensal gut flora, and there appear to be substantial differences in the diversity and composition in patients who respond to ICT versus nonresponders (205,206).”

Studies in humans and mice of gut microbes that stratify therapy response often report differing taxonomic findings that survive uniform bioinformatic re-analysis, though functional profiles agree more.

“Moreover, observations in humans and mice of gut microbes that stratify therapy response, particularly immunotherapy (16, 17, 21, 26), have not uncommonly shown varying taxonomic differences that persist despite uniform bioinformatic re-analyses, although there is greater concordance when examining functional profiles (161, 162).”

Commensal microbiota can affect outcomes of immunotherapeutic interventions in human cancers.

“Recent data have shown that commensal microbiota can affect the outcomes of immunotherapeutic interventions in human cancers (Gopalakrishnan et al., 2018; Routy et al., 2018).”

The microbiome influences tumor immunity and the response to immune checkpoint inhibitors.

“The microbiome has been described to majorly impact tumor immunity and response to ICI10–17”

In germ-free mice, FMT from patients can change anti-tumor immunity and the response to ICI therapy.

“and additionally showed that modulation of the gut microbiome of germ-free mice via FMT from patients could alter anti-tumor immunity and response to ICI therapy in gnotobiotic mice11–13.”

Patients who respond to ICI therapy and those who do not have distinct bacterial signatures in their gut microbiome.

“Previously, we demonstrated that differential bacterial signatures comprise the gut microbiome of responders versus non-responders to ICI therapy”

The gut microbiota influences the clinical responses of cancer patients to immune-checkpoint inhibitors (ICIs).

“The gut microbiota influences the clinical responses of cancer patients to immunecheckpoint inhibitors (ICIs).”

Clinical benefit to immune-checkpoint inhibitors or chimeric antigen receptor-T cell therapy has been linked to the presence or absence of distinct intestinal commensals across various malignancies.

“Indeed, clinical benefit to immune-checkpoint inhibitors (ICIs) or chimeric antigen receptor-T cell therapy has been linked to the presence or absence of distinct intestinal commensals across various malignancies.”

SIG2 contained Lachnospiraceae (species from the genus Blautia, Roseburia, Dorea, and Eubacterium) and Oscillospiraceae family members (Faecalibacterium prausnitzii, Ruminococcus bicirculans, and R. lactaris), which were previously associated with general health and favorable clinical responses to ICIs.

“SIG2 contained Lachnospiraceae (species from the genus Blautia, Roseburia, Dorea, and Eubacterium) and Oscillospiraceae family members (Faecalibacterium prausnitzii, Ruminococcus bicirculans, and R. lactaris), which were previously associated with general health and favorable clinical responses to ICIs.”

The species in SIG2 are strongly associated with healthy status and favorable clinical responses.

“Instead, SIG2 was composed of 45 species gathering Lachnospiraceae and Oscillospiraceae family members that are strongly associated with healthy status and favorable clinical responses.4”

A high level of F. prausnitzii is associated with a positive response to ICI in multiple cancer types.

“A high level of Faecalibacterium prausnitzii have been associated with a positive response to ICI in multiple cancer types.”

In 43 metastatic melanoma patients treated with anti-PD-1, high F. prausnitzii relative abundance was the strongest signal of response to ICI.

“Simultaneously, a second study on 43 patients with metastatic melanoma treated with anti-PD-1 agents showed the same results, with high F. prausnitzii relative abundance reported as the strongest signal of response to ICI.6”

Multiple studies reported significant differences in microbial diversity and composition between responding and non-responding melanoma, NSCLC, and RCC patients treated with anti-PD-1 alone or with anti-CTLA-4.

“Multiple studies have reported significant differences in microbial diversity and composition between responding and non-responding melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients treated with anti-PD-1 alone or in combination with anti-CTLA-4 agents (ipilimumab).2,4-8”

New results in two independent cohorts, together with previous studies, confirm high baseline F. prausnitzii abundance is predictive of positive response to ICI in multiple cancer types.

“These new results in two independent cohorts, together with previous studies,4,6,9,11,12,14,15 confirm that a high abundance of F. prausnitzii in stools at baseline is predictive of a positive response to ICI in multiple cancer types.”

Meta-analysis found high abundance of Faecalibacterium genus was strongest signal associated with response to ICI using anti-PD-1 or anti-CTLA-4.

“A meta-analysis found that high abundance of Faecalibacterium genus was the strongest signal associated with response to ICI, using either anti-PD-1 or anti-CTLA-4 antibodies.5–7,12,13”

Increasing evidence suggests abundance of F. prausnitzii in gut may impact clinical response to ICI across multiple cancers.

“There is thus increasing evidence to suggest that the abundance of F. prausnitzii in the gut may impact clinical response to ICI across multiple cancers.”

In that context, positive response to ICI was associated with higher F. prausnitzii levels.

“Interestingly, the positive response to ICI in this context was also associated with higher F. prausnitzii levels.6”

Mice colonized with microbiota from ICI responders had better response to ICI in melanoma model than those colonized with non-responders.

“A causality link was then established by showing that mice colonized with microbiota from human patients that responded to ICI had a better response to ICI in a melanoma model than their counterparts colonized with the microbiota from non-responders.6”

The gut microbiota has been involved in response to cancer treatments, and in particular to immunotherapy.

“In this context, the gut microbiota has been involved in response to cancer treatments, and in particular to immunotherapy.2,6,7,32”

In patients with cancer, specific taxa, including F. prausnitzii, A. muciniphila and Bifidobacteria, have been associated with improved clinical responses to ICI.

“In patients with cancer, specific taxa, including F. prausnitzii, A. muciniphila and Bifidobacteria, have been associated with improved clinical responses to ICI.2,6,7”

Gut microbiota influence anti-tumor responses in preclinical models and in patients with melanoma, renal cell carcinoma, and NSCLC.

“The effects of the gut microbiota on the anti-tumor response has been demonstrated in preclinical models as well as in patients with melanoma, renal cell carcinoma and NSCLC”

The gut and tumor microbiome are associated with anti-tumor responses and, in some cases, with response to immune checkpoint blockade.

“The gut and tumor microbiome have been associated with anti-tumor responses and, in some cases, response to immune checkpoint blockade”

Tumor-challenged mice that received fecal microbiota transplantation from patients responsive to anti-PD-1 had significantly reduced tumor growth compared with mice receiving fecal microbiota transplantation from nonresponders.

“Tumor-challenged mice that received FMT from patients responsive to anti-PD-1 had significantly reduced tumor growth compared with mice receiving FMT from nonresponders (Derosa et al., 2020; Gopalakrishnan et al., 2018; Routy et al., 2018b).”

Certain bacteria are linked to favorable immune checkpoint blockade outcomes, including Akkermansia muciniphila, Faecalibacterium prausnitzii, and Bifidobacterium spp., particularly Bifidobacterium longum.

“Certain bacteria are linked to favorable outcomes, including the mucin-consuming anaerobic bacterium Akkermansia muciniphila (Derosa et al., 2022; Routy et al., 2018b), Faecalibacterium prausnitzii (Gopalakrishnan et al., 2018), and Bifidobacterium spp. (Sivan et al., 2015), particularly Bifidobacterium longum (Matson et al., 2018).”

Seminal 2018 studies demonstrated direct links between gut microbiota composition and the success of immune checkpoint blockade in melanoma, non-small-cell lung cancer, urothelial, and kidney cancers.

“Thomas Gajewski in Chicago, Jennifer Wargo at the MD Anderson Cancer Centre, and our laboratory at the Gustave Roussy Cancer Centre in Paris later published seminal studies in the same 2018 issue of Science, demonstrating direct links between gut microbiota composition and the success of ICB in different cancer populations, including melanoma, non–small-cell lung cancer (NSCLC), and urothelial and”

Immunotherapy responders possess greater microbial diversity as shown by indices like Shannon or Chao1.

“However, although indices like Shannon or Chao1 can show that immunotherapy responders possess greater microbial diversity (Gopalakrishnan et al., 2018), it has become clear that these metrics alone do not fully capture how individual taxa drive or mitigate disease outcomes, as evident in lung or kidney cancer patients (Gupta et al., 2020).”

Higher abundances of Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium stimulate a more favorable T cell-mediated response to anti-PD-1 therapy in preclinical models and patients with metastasized melanoma.

“higher abundances of the commensals Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium stimulate a more favorable T cell-mediated response to anti-PD-1 therapy in both preclinical models and patients suffering from metastasized melanoma.190–192”

Broad-spectrum antibiotic treatment reduced intestinal abundances of Roseburia, Bifidobacterium, or Ruminococcus spp.

“For instance, broad-spectrum antibiotic treatment reduced the intestinal abundances of microbes in our patients such as Roseburia, Bifidobacterium or Ruminococcus spp., which were previously associated with beneficial outcomes of ICB cancer immunotherapies1,36.”

The gut microbiome may influence how well cancer immunotherapy works.

“Increasing evidence suggests that the gut microbiome may modulate the efficacy of cancer immunotherapy.”

Akkermansia muciniphila, Faecalibacterium prausnitzii and Bifidobacterium longum have been linked to better responses to immune checkpoint blockade.

“Gut microbes such as Akkermansia muciniphila, Faecalibacterium prausnitzii and Bifidobacterium longum have been associated with improved responses to immune checkpoint blockade (ICB)1–3”

Broad-spectrum antibiotics reduced intestinal abundances of Roseburia, Bifidobacterium, or Ruminococcus spp., which had previously been linked to beneficial ICB outcomes.

“For instance, broad-spectrum antibiotic treatment reduced the intestinal abundances of microbes in our patients such as Roseburia, Bifidobacterium or Ruminococcus spp., which were previously associated with beneficial outcomes of ICB cancer immunotherapies1,36.”

Evidence is accumulating that the microbiome affects how cancer therapy works.

“There is mounting evidence supporting the role of the microbiome in response to cancer therapy”

Recent studies show that the gut microbiome influences response to immune checkpoint blockade across multiple cancer types.

“several recent studies demonstrating the influence of the gut microbiome specifically on the response to immune checkpoint blockade across cancer types”

In metastatic melanoma, non-responders to anti-PD-1 had lower gut bacterial diversity and higher abundance of Bacteroidales.

“NR had significantly lower diversity of gut bacteria and higher abundance of Bacteroidales”

In metastatic melanoma, responders to anti-PD-1 had higher gut bacterial diversity and higher relative abundance of Clostridiales, Ruminococcaceae and Faecalibacterium.

“patients who responded to anti-PD-1 therapy had a significantly higher diversity of bacteria in their gut microbiota as well as a higher relative abundance of Clostridiales, Ruminococcaceae, and Faecalibacterium”

Patients with a favorable gut microbiota had increased expression of cytolytic T cell markers and antigen processing and presentation in the tumor microenvironment compared with patients with an unfavorable microbiota.

“patients with a “favorable” gut microbiota had increased expression of cytolytic T cell markers and antigen processing and presentation compared to patients with “unfavorable” gut microbiota”

Multiple recent studies show that the gut microbiota plays a role in patients receiving immune checkpoint blockade.

“multiple studies published in the past several months demonstrating a role for the gut microbiota in patients on immune checkpoint blockade”

Germ-free mice receiving FMT from responders had delayed tumor outgrowth and enhanced response to immune checkpoint blockade.

“mice receiving FMT from R had significantly delayed tumor outgrowth and enhanced response to treatment with immune checkpoint blockade”

Bacterial taxa in the Ruminococcaceae family of Firmicutes, such as F. prausnitzii, are associated with both response and toxicity to immune checkpoint blockade across studies.

“Bacterial taxa within the Ruminococaceae family of the Firmicutes phylum (such as F. prausnitzii) have been associated with both response and toxicity to immune checkpoint blockade across studies”

Certain Bacteroidetes taxa have been linked to response to cancer immunotherapy, including Akkermansia muciniphila, Bifidobacterium longum, Bifidobacterium adolescentis, and Colinsela aerofaciens, while others such as Actinomyces viscosus and Gardnerella vaginalis have been linked to non-response.

“Bacteroidetes have also been associated with response (such as Akkermansia muciniphila, Bifidobacterium longum and Bifidobacterium adolescentis, and Colinsela aerofaciens) and non-response (such as Actinomyces viscosus, Garnderella vaginalis) (Frankel et al., 2017, Gopalakrishnan et al., 2018, Matson et al., 2018, Routy et al., 2018).”

Bacteroidales taxa are associated with lack of response to immune checkpoint blockade, while higher abundance of these taxa is generally associated with lower toxicity.

“bacterial taxa within the Bacteroidales order of the Bacteroidetes phylum have been associated with a lack of response to immune checkpoint blockade (Bacteroidales), while a higher abundance of these taxa within the gut are also generally associated with a lower incidence of toxicity”

The microbiota is emerging as a determinant of responses to various anticancer therapies, including immunotherapy.

“The microbiota is emerging as a determinant of responses to various anticancer therapies, including immunotherapy122–125.”

Similar microbiome findings for anti-PD-1 therapy have been reported, though different microbes are implicated.

“Similar findings for anti-PD-1 therapy have been reported, although different microbes have been implicated (100, 101).”

Significant differences in microbial diversity and composition have been noted between responding and non-responding melanoma patients treated with anti-PD-1 therapy; different studies suggest different species may be enriched in responding versus non-responding patients.

“Significant differences in microbial diversity and composition have been noted between responding and non-responding melanoma patients treated with anti-PD-1 therapy; different studies suggest different species may be enriched in responding versus non-responding patients [30, 31].”

Mice transplanted with stool from responding patients had higher levels of CD8 T-cell concentrations in the gut than those transplanted with stool from non-responders.

“Furthermore, mice transplanted with stool from responding patients also had higher levels of CD8 T-cell concentrations in the gut than those transplanted with stool from non-responders.”

Mice transplanted with stool from patients responding to anti-PD-1 antibodies had higher levels of CD8 T-cell density in tumor tissue.

“Mice that were transplanted with stool from patients responding to anti-PD-1 antibodies had higher levels of CD8 T-cell density in tumor tissue.”

IRAE sites associated with ICI efficacy may have more to do with shared antigens between tumor and involved site rather than any intrinsic association between checkpoint inhibitor and IRAE site.

“A recent publication cited above suggests IRAE sites associated with ICI efficacy may have more to do with shared antigens between tumor and involved site rather than any intrinsic association between checkpoint inhibitor and IRAE site [30].”

Clostridiales/Ruminococcaceae/Faecalibacterium were abundant in responders and Bacteroidales/Escherichia coli in non-responders.

“They showed an abundance of Clostridiales/Ruminococcaceae/Faecalibacterium in R and Bacteroidales/Escherichia coli in NR (Figure 2) (57).”

Higher multiplicity of bacteria was found in patients with prolonged PFS.

“Moreover, Gopalakrishnan et al. (57) evaluated the oral and gut microbiome of 112 melanoma patients treated with PD-1 blockade via 16S sequencing and discovered a higher multiplicity of bacteria in patients with prolonged PFS.”

Patients with more non-responder microorganisms often had a shortened PFS and a higher level of Tregs with a blunted cytokine response.

“In contrast, patients with more NR microorganisms often had a shortened PFS and a higher level of Tregs with a blunted cytokine response.”

Transplantation of fecal microbiota from responders delayed tumor growth, increased the accumulation of CXCR3CD4+ T cells and CD8+ T cells, and upregulated PD-L1 expression in the TME, thereby counteracting the impaired anticancer ability against PD-L1 blockade.

“Compared to NR-FMT mice, transplantation of fecal microbiota from R patients delayed tumor growth, increased the accumulation of CXCR3CD4+ T cells and CD8+ T cells, and upregulated PD-L1 expression in the TME, thereby counteracting the impaired anticancer ability against PD-L1 blockade.”

Patients with more Faecalibacterium had a significantly prolonged PFS with higher level of effector T cells and a stabilized cytokine response to PD-1 blockade.

“Patients with more Faecalibacterium also had a significantly prolonged PFS with higher level of effector T cells and a stabilized cytokine response to PD-1 blockade.”

Multiple translational studies published in 2018 support a pivotal role of the gut microbiome in modulating the response to immune checkpoint blockade.

“Multiple translational studies, published in 2018, further support the pivotal role of the gut microbiome in modulating the response to immune checkpoint blockade [170,171,172].”

FMT in germ-free mice with the identified bacteria along with anti-PD1 therapy enhanced anti-cancer effects and reduced melanoma growth.

“Functional studies performed with FMT in germ free mice further demonstrated how treating mice with the identified bacteria, along with the anti-PD1 therapy, enhanced the anti-cancer effects and reduces the melanoma growth [171].”

Gopalakrishnan et al. demonstrated through metagenomics of melanoma patients' fecal samples that anti-PD1 responders' microbiome differed in composition from non-responders.

“In parallel, Gopalakrishnan et al. [171] demonstrated through metagenomics analysis of melanoma patients’ fecal samples that the anti-PD1 responders’ microbiome was different in composition compared with that of non-responders.”

Patients' microbiome composition is linked with the intrinsic efficacy of immune checkpoint inhibitor-based immunotherapy in different solid tumors.

“Given the multiplicity of effects that gut microbiome may play on the host’s immune system, it is not surprising that emerging studies strongly linked the patients’ microbiome composition with the intrinsic efficacy of immune checkpoint inhibitors-based immunotherapy, in the treatments of different solid tumors [170,171,172].”

An increase in the abundance of Clostridiales, Ruminococcaceae and Faecalibacteriae was observed in patients' gut microbiome.

“The authors observed in patient’s gut microbiome an increase in the abundance of Clostridiales, Ruminococcaceae and Faecalibacteriae.”

Patient stratification on the basis of gut microbiome composition may be important to identify responders and nonresponders to immunotherapy for the treatment of epithelial tumors and melanomas.

“recent studies confirm the potential importance of patient stratification on the basis of gut microbiome composition to identify responders and nonresponders to immunotherapy for the treatment of epithelial tumors and melanomas (Gopalakrishnan et al., 2018;Jobin, 2018;Routy et al., 2018)”

Manipulating gut microbiota composition could improve the response to α-PD-1/PD-L1.

“Besides, manipulating gut microbiota composition could improve the response to α-PD-1/PD-L1 [311, 314–316].”