The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients

Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy.

“Besides, reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy.14”

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]”

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].”

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].”

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.”

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].”

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,”

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.”

In preclinical models, transplantation of fecal material enriched with Bifidobacterium spp. alone, even without checkpoint inhibitors, is sufficient to delay tumor growth.

“in preclinical models, transplantation of fecal material enriched with Bifidobacterium spp. alone (even without CPIs) was sufficient to delay tumor growth4,5.”

The intestinal microbiota directly impacts the efficacy of specific cancer immune therapies.

“The intestinal microbiota has been shown to directly impact on the efficacy of specific cancer immune therapies1–3.”

The gut microbiome modifies immune checkpoint inhibitor treatment response.

“Multiple landmark studies have identified a role for the gut microbiome in modifying ICI treatment response1,2”

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).”

Broad-spectrum antibiotics significantly abrogated anti-PD-1-induced tumour reduction.

“As previously reported1,2, broad-spectrum antibiotics significantly abrogated anti-PD-1-induced tumour reduction”

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 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”

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).”

The bacterial genus Enterococcus is enriched in responding patients treated with immunotherapies targeting PD-1.

“Multiple analyses of the commensal microbiome from human cohorts treated with immunotherapies targeting PD-1 have revealed that the bacterial genus Enterococcus is enriched in responding patients (12, 13).”

Potential NlpC/p60 orthologs in other genera such as Lactobacillus may offer additional microbiota correlations for predicting and improving patient outcomes.

“the detection of potential NlpC/p60 orthologs in other genera such as Lactobacillus (Fig. 2C, Table S5), which has also been identified in immunotherapy-responsive patients (13), may provide additional specific microbiota correlations to predict and improve patient outcomes.”

The increase in OVA-specific CD8+ T cells is consistent with enhanced priming of a tumor antigen-specific immune response.

“consistent with enhanced priming of a tumor antigen-specific immune response (9, 13).”

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

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

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.”

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.”

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.”

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”

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.”

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.”

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.”

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.”

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”

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.”

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).”

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.”

B. thetaiotaomicron was reported as enriched in responders in the Frankel and Matson cohorts.

“In contrast, B. thetaiotaomicron was reported as enriched in R in the Frankel and Matson cohorts (5,7) whereas, using a consistent re-analysis approach for all cohorts, this species was enriched in NR.”

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).”

Melanoma patients treated with anti-PD-L1 had higher levels of Bifdobacterium longum, Collinsella aerofaciens, and Enterococcus faecium, highlighting the importance of the microbiome.

“Furthermore, melanoma patients treated with anti-PD-L1 had higher levels of Bifdobacterium longum, Collinsella aerofaciens, and Enterococcus faecium, highlighting the importance of the microbiome [122].”

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”

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).”

Particular antitumor effects of microbiota have been linked to altered T cell activation or recruitment into tumors or tumor-draining lymph nodes.

“Specific antitumor effects of microbiota have been associated with changes in T cell activation and/or recruitment into the tumor or tumor-draining lymph nodes (Matson et al., 2018; Routy et al., 2018; Shi et al., 2020a; Sivan et al., 2015; Tanoue et al., 2019; Vetizou et al., 2015).”

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”

Bifidobacterium-treated mice showed increased IFN-γ production, followed by stronger tumor-specific T cell responses and slower tumor growth.

“Bifidobacterium-treated mice showed increased IFN-γ production, followed by stronger tumor-specific T cell responses and slower tumor growth [36].”

Recolonized germ-free mice with fecal samples from responders or dominant microbiota in responders could improve antitumor effects of ICIs.

“Recolonized germ-free mice with fecal samples from responders or dominant microbiota in responders could improve antitumor effects of ICIs [36, 94].”

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).”

The composition of the commensal microbiota in patients is associated with the therapeutic efficacy of anti-PD-1 monoclonal antibody.

“The composition of the commensal microbiota in patients is associated with the therapeutic efficacy of anti-PD-1 monoclonal antibody.42”

The composition of gut microbiota may dictate, at least in part, the anticancer activity of immune checkpoint inhibitors.

“Very recent reports highlighted that the composition of gut microbiota may dictate, at least in part, the anticancer activity of ICI.”

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”

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”

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.”

Health-associated or immunogenic bacteria were more abundant in responding patients.

“Given these considerations, it is perhaps even more striking that bacteria generally associated with health (such as Clostridiales, Ruminococcacae, Faecalibacterium spp., Akkermansia muciniphila, B. fragilis,a n dBifidobacteria) (13, 14, 18-20) or immunogenicity (Enterococci, Collinsella, and Alistipes)( 11, 13, 14, 20) were found to be abundant in responding patients.”

In patients receiving PD-1 blockade, the balance between bacteria considered favorable and unfavorable distinguishes those who respond from those who do not.

“One of the striking findings that distinguishes cancer patient responders from nonresponders after PD-1 blockade immunotherapy is the ratio of putatively favorable to unfavorable bacteria (20).”

FMT from immune checkpoint blockade responders transferred a responder phenotype to mice, while nonresponder feces tended to transfer nonresponsiveness.

“Notably, fecal microbial transplantation (FMT) o ff e c e sf r o mp a t i e n t s( w h os h o w e dc l i n i c a lr esponse to immune checkpoint blockade) transferred a”

16S rRNA gene amplicon and shotgun DNA sequencing of patient stool identified bacterial subsets more abundant in responders than nonresponders.

“16S ribosomal RNA (rRNA)-based sequencing of gene amplicons and shotgun DNA sequencing of patient stool samples have identified subsets of bacteria more abundant in responding versus nonresponding patients.”

Bifidobacteria, Akkermansia muciniphila, E. hirae, and Bacteroides have been reported to enhance antitumor T cell responses and improve tumor control in vivo.

“To date, Bifidobacteria spp.(15, 20), Akkermansia muciniphilia (14), E. hirae (16), and Bacteroides spp.(13) have been shown to improve antitumor T cell responses and support better tumor control in vivo.”

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”

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”

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”

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”

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”

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”

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”

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”

These microbes had previously been reported to be associated with better ICB immunotherapy response.

“These microbes were also previously reported to be associated with better response to ICB immunotherapy2,3,38,39.”

These effects were mediated by increased CD8+ T cell densities and reduced FoxP3+CD4+ Tregs in the tumor microenvironment.

“These effects were mediated by increased densities of CD8+ T-cells and reduced FoxP3+CD4+ Tregs in the tumor microenvironment”

Transfer of responder stool to germ-free mice recapitulated the phenotype, with slower tumor growth and improved anti-PD-L1 efficacy compared with non-responder stool.

“mice that received responder-stool growing tumors at slower rate and having markedly improved efficacy to anti-PD- L1 immunotherapy when compared to mice that received non-responder stool”

In metastatic melanoma, responders to anti-PD-1 had enrichment of Bifidobacterium longum, Collinsella aerofaciens and Enterococcus faecium in baseline fecal samples.

“patients who responded to anti-PD-1 therapy had enrichment of Bifidobacterium longum, Collinsella aerofaciens and Enterococcus faecium in baseline fecal samples”

At lower taxonomic levels, the general patterns do not hold: some Firmicutes taxa such as Roseburia and Streptococcus are associated with lack of response, and some Bacteroidetes taxa such as Alistipes, Porphyromonas pasteri and Colinsella aerofaciens are associated with response.

“at lower levels of taxonomy within these phyla these generalizations do not apply, as some taxa within Firmicutes have been associated with a lack of response (Roseburia, Streptococcus)”

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).”

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.”

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.”

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.”

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].”

In patients with metastatic melanoma before PD-1 blockade, the clinical response rate was 38%, with 16 responders and 26 non-responders.

“They collected stool materials from 42 patients with metastatic melanoma before administering PD-1 blockade, and the clinical response rate was 38%, showing that there were 16 responders (R) and 26 non-responders (NR).”

PD-1 inhibitor exerted its antitumor activity in mice colonized with R bacteria but was ineffective in NR bacteria colonized mice.

“As expected, PD-1 inhibitor exerted its antitumor activity in mice colonized with R bacteria but was ineffective in NR bacteria colonized mice, thus confirming in vivo the influence of gut microbiome on human immunity.”

Ten bacterial species differed between responders and non-responders, and 8 of those were more abundant in responders, including Bifidobacterium.

“The authors selected 10 bacterial species that were different between R and NR, 8 of those were found to be more abundant in R (including Bifidobacterium, also observed in preclinical studies).”

A ratio of over 1.5 of beneficial to non-beneficial operational taxonomic units indicated clinical benefit.

“For instance, some researchers calculated the proportion of “beneficial” and “non-beneficial” operational taxonomic units and their ratio for every patient and reached a limit conclusion—a ratio of over 1.5 indicated clinical benefit (55).”

Matson et al. metagenomics characterization of stools from melanoma patients treated with immune checkpoint inhibitors corroborated that responders showed a different microbiome compared to non-responders.

“Along the same line, Matson et al. [172] performed a metagenomics characterization of stools samples from melanoma patients treated with immune checkpoint inhibitors, further corroborating the finding that responders showed a different microbiome compared to those not responding to therapy.”

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].”

Bifidobacterium longum, Enterococcus faecium and Collinsella aerofaciens are important in ameliorating anti-PD-L1 efficacy, as functionally proven in vivo.

“They identified and functionally proven in vivo the importance of Bifidobacterium longum, Enterococcus faecium and Collinsella aerofaciens in ameliorating anti-PD-L1 efficacy [172].”

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].”

The gut microbiota of immunotherapy-sensitive patients was distinct from that of immunotherapy-resistant populations.

“It was reported that the gut microbiota of immunotherapy-sensitive patients was distinct from that of immunotherapy-resistant populations [311, 312].”