Resistance to anti-PD-1 immunotherapy can be attributed to the gut microbiome

Immunotherapies (Immune Checkpoint Inhibitors, ICI) have become a powerful therapeutic strategy for treating a variety of cancers. It is a very exciting area but with challenges. Indeed, the patient response to these therapies is often heterogeneous and not durable, with only 20 to 40% of patients actually responding. Because these drugs can trigger severe auto-immune reactions, predicting who will be a non-responder will not only save treatment costs but spare patients from side effects.

Resistance to ICI has been attributed to multiple host factors such as low mutational burden, poor intrinsic antigenicity of tumor cells, and functional exhaustion of tumor-infiltrating lymphocytes. But more recently, factors beyond tumor genomics have emerged, including the gut microbiota, which could influence antitumor immune response through innate and adaptive immunity.

First evidence, from preclinical studies, of gut microbiota implication in immunotherapy effectiveness

Routy and colleagues compared the therapeutic efficacy of PD-1 mAb alone or combined with CTLA-4mAb in mice with established MCA-205 sarcoma and RET melanoma. To determine the influence of gut microbiota on treatment efficacy, mice were treated with antibiotics or left untreated. Antibiotic treatment significantly compromised the antitumor effects and survival of mice treated with PD-1 mAb alone or in combination with CTLA-4 mAb.

Several preclinical studies have shown that the composition of the gut microbiota can exert a major influence on immunotherapy response. Mice with a favorable gut microbiota showed far greater therapeutic activity of anti-PD-1 treatment, and this benefit can be transferred by cohousing or fecal transplantation.

Clinical evidence that gut microbiota composition is associated with immunotherapy response in cancer patients

Cancer patients treated with antibiotics have shorter progression-free survival and overall survival. Together, with the preclinical evidence, this prompted the analysis of the human gut microbiota in association with the therapeutic efficacy of immunotherapies.

In 2018, 3 publications in Science showed the importance of gut microbiota in immunotherapy effectiveness in patients with melanoma (Matson et al. and Gopalakrishnan et al.) and epithelial tumors (Non-Small Cell Lung Cancer, NSCLC and Renal Cell Cancer, RCC) (Routy et al.).

When segregating responders from non-responders to anti-PD-1, differences in gut microbiota were observed, including, but not limited to, an enrichment in Akkermansia muciniphila in patients with NSCLC or RCC showing the best clinical outcomes and Faecalibacterium in responders with melanoma. In another study, Matson and colleagues found that 8 species were enriched in responding patients with melanoma, namely Enterococcus faecium, Collinsella aerofaciens, Bifidobacterium adolescentis, Klebsiella pneumoniae, Veillonella parvula, Parabacteroides merdae, Lactobacillus sp., and Bifidobacterium longum. Bifidobacteriaceae family members were previously associated with improved immune-mediated tumor control and efficacy of anti–PD-L1 therapy in mice.

On the other hand, Bacteroides thetaiotaomicron, Escherichia coli, Anaerotruncus colihominis, Ruminococcus obeum, and Roseburia intestinalis were associated with non-responding patients with melanoma.

Back to preclinical models to better understand the cause-effect relationship between immunotherapy efficacy and gut microbiota

Fecal microbiota transplantation (FMT) using patient stool into germ-free and/or antibiotic-treated mice was used to better understand the cause-effect relationship between immunotherapy efficacy and gut microbiota. Mice receiving FMT from responder patients exhibited reduced tumor size, improved response to anti-PD-1, and a higher density of CD8+ T cells in the tumor microenvironment. Whereas FMT from non-responder patients conveyed resistance to anti-PD-1 treatment.

Modulation of the gut microbiome composition could restore the efficacy of anti-PD1 treatment. For example, the administration of A. muciniphila in mice reinstated the anticancer effects of PD-1 blockade that were previously inhibited by antibiotic treatment.

Multiple specific bacteria may contribute to improved antitumor immunity in mouse models and in patients. On the other hand, several bacteria were also overrepresented in non-responders, suggesting that other commensal members of the gut microbiota may have immune-inhibitory effects.

The gut microbiota markedly influences the outcome of immunotherapy, so opens the way to new biomarkers for predicting patient response to immune checkpoint inhibitors and new therapeutic strategies by modulating the microbiota to expand immunotherapy efficacy.

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

Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236. Epub 2017 Nov 2. PMID: 29097493; PMCID: PMC5827966.

Abstract :

Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we examined the oral and gut microbiome of melanoma patients undergoing anti–programmed cell death 1 protein (PD-1) immunotherapy (n = 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (n = 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (P < 0.01) and relative abundance of bacteria of the Ruminococcaceae family (P < 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.

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

Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF.. Science. 2018 Jan 5;359(6371):104-108. doi: 10.1126/science.aao3290. PMID: 29302014; PMCID: PMC6707353.

Abstract :

Anti–PD-1–based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential composition of the patients’ microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclinical mouse models. We analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16S ribosomal RNA gene sequencing, metagenomic shotgun sequencing, and quantitative polymerase chain reaction for selected bacteria. A significant association was observed between commensal microbial composition and clinical response. Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium. 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. Our results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients.

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Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.

Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragón L, Jacquelot N, Qu B, Ferrere G, Clémenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Science. 2018 Jan 5;359(6371):91-97. doi: 10.1126/science.aan3706. Epub 2017 Nov 2. PMID: 29097494.

Abstract :

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12–dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.

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