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A Microbiota-Derived Metabolite Augments Cancer Immunotherapy Responses in Mice

2020; Cell Press; Volume: 38; Issue: 4 Linguagem: Inglês

10.1016/j.ccell.2020.09.005

1878-3686

Emma Allen‐Vercoe, Bryan Coburn,

Adenosine and Purinergic Signaling

Improving the rate of patient response to immune checkpoint blockade therapy is a current clinical goal. An article published in Science suggests that some members of the gut microbiome may provide a key molecule toward this end. Improving the rate of patient response to immune checkpoint blockade therapy is a current clinical goal. An article published in Science suggests that some members of the gut microbiome may provide a key molecule toward this end. The immune system, and in particular cytotoxic T cells, are critical for control of tumor growth and responses to anti-tumor therapy. Immune checkpoint blockade (ICB) therapy de-represses T cell response to tumors and is a highly successful mode of cancer treatment for some cancers. However, many patients show either primary or acquired resistance to ICB, the basis of which is incompletely understood. Seminal research by several groups has established that one determinant of response to ICB therapy lies in the gut microbiota of patients and that members of this eclectic group of microbes are causally implicated in ICB response (reviewed by Frankel et al., 2019Frankel A.E. Deshmukh S. Reddy A. Lightcap J. Hayes M. McClellan S. Singh S. Rabideau B. Glover T.G. Roberts B. Koh A.Y. Cancer immune checkpoint inhibitor therapy and the gut microbiota.Integr. Cancer Ther. 2019; (Published online April 23, 2019)https://doi.org/10.1177/1534735419846379Crossref PubMed Scopus (22) Google Scholar). However, the mechanisms behind the microbiome-driven responsiveness are unclear. Mager et al. have now revealed that one mechanism linking the gut microbiome and response to ICB therapy in mice is the presence of a microbially produced purine nucleoside molecule—inosine (Mager et al., 2020Mager L.F. Burkhard R. Pett N. Cooke N.C.A. Brown K. Ramay H. Paik S. Stagg J. Groves R.A. Gallo M. et al.Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy.Science. 2020; (Published online August 13, 2020)https://doi.org/10.1126/science.abc3421Crossref PubMed Scopus (5) Google Scholar). Purines are essential components of both mammalian and microbial metabolism, and among their many functions they are especially important as signaling molecules and carriers of cellular energy. Bacteria generally produce purines through de novo synthesis or from the salvage of nucleotides from the environment and maintain these as intracellular pools; some are excreted through fermentative pathways (Ledesma-Amaro et al., 2013Ledesma-Amaro R.J.A. Santos M.A. Revuelta J.L. Biotechnological production of feed nucleotides by microbial strain improvement.Process Biochem. 2013; 48: 1263-1270Crossref Scopus (18) Google Scholar). Mager et al. isolated bacterial strains from homogenized tumor tissue from mice with chemically induced colonic cancer either treated or not treated with ICB therapy. Species enriched in ICB-treated tumor tissues compared to untreated controls include the anaerobes Bifidobacterium pseudolongum and Akkermansia muciniphila; the same or similar gut resident species have previously been independently associated with enhanced response to ICB therapy in humans (Matson et al., 2018Matson V. Fessler J. Bao R. Chongsuwat T. Zha Y. Alegre M.L. Luke J.J. Gajewski T.F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.Science. 2018; 359: 104-108Crossref PubMed Scopus (922) Google Scholar; Routy et al., 2018Routy B. Le Chatelier E. Derosa L. Duong C.P.M. Alou M.T. Daillère R. Fluckiger A. Messaoudene M. Rauber C. Roberti M.P. et al.Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors.Science. 2018; 359: 91-97Crossref PubMed Scopus (1725) Google Scholar). They then demonstrate that the presence of either of these two species in the gut microbiota boosts a dendritic cell-dependent effector T cell circuit that enhances the effect of ICB therapy (Figure 1) (Mager et al., 2020Mager L.F. Burkhard R. Pett N. Cooke N.C.A. Brown K. Ramay H. Paik S. Stagg J. Groves R.A. Gallo M. et al.Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy.Science. 2020; (Published online August 13, 2020)https://doi.org/10.1126/science.abc3421Crossref PubMed Scopus (5) Google Scholar). The effector molecule involved in this mechanism is determined to be inosine, acting through a signaling pathway initiated by binding of the molecule to adenosine 2A receptors (A2AR) on T cells (Figure 1). In vitro, physiologic concentrations of inosine, but not adenosine, enhance Th1 differentiation and effector function of naive T cells that express A2AR. Intriguingly, this enhanced differentiation is dependent on the presence of IFNγ; when this cytokine is absent, inosine acts to inhibit Th1 differentiation. Adoptive transfer of T cells lacking A2AR into Rag1-deficient mice decreases ICB response to inosine-producing bacterial species. Importantly, the ICB-promoting effects of these bacteria and supplementary inosine are context dependent: in the absence of treatment with CpG, a widely used anti-tumor adjuvant, inosine results in larger tumors and decreases anti-tumor immunity, rather than improving ICB response, indicating that the beneficial effect of inosine requires T cells to be co-stimulated (for example, by dendritic cells expressing TLR9, a molecule which, in turn, specifically recognizes CpG). Overall, the authors note that the newly revealed beneficial effects of inosine are especially important to consider in the context of ongoing investigation of A2AR inhibition for cancer treatment (Mager et al., 2020Mager L.F. Burkhard R. Pett N. Cooke N.C.A. Brown K. Ramay H. Paik S. Stagg J. Groves R.A. Gallo M. et al.Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy.Science. 2020; (Published online August 13, 2020)https://doi.org/10.1126/science.abc3421Crossref PubMed Scopus (5) Google Scholar). Enhanced T cell signaling and activation may not be the only factors involved in the stimulation of T cell immunity in the tumor environment by inosine. Within tumors, cancer cells rapidly deplete glucose such that infiltrating T cells, which require abundant energy substrates for full function, would have been outcompeted if alternative substrates were not present. Earlier this year, effector T cells were demonstrated to utilize inosine as an alternative source of energy to glucose within the tumor microenvironment; the combination of inosine supplementation and administration of anti-PDL1 antibody led to delayed tumor growth and increased survival time in a mouse model of melanoma (Wang et al., 2020Wang T. Gnanaprakasam J.N.R. Chen X. Kang S. Xu X. Sun H. Liu L. Rodgers H. Miller E. Cassel T.A. et al.Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction.Nat. Metab. 2020; 2: 635-647Crossref PubMed Scopus (26) Google Scholar). However, some cancer cells are also able to use inosine as an energy source. When T cells compete with cancer cells for inosine in vitro, the beneficial effect of inosine supplementation together with ICB treatment is lost (Wang et al., 2020Wang T. Gnanaprakasam J.N.R. Chen X. Kang S. Xu X. Sun H. Liu L. Rodgers H. Miller E. Cassel T.A. et al.Inosine is an alternative carbon source for CD8+-T-cell function under glucose restriction.Nat. Metab. 2020; 2: 635-647Crossref PubMed Scopus (26) Google Scholar). Taken together, an inosine-mediated T cell antitumor immunity boost might be achieved through both signaling activation and metabolic rewiring (Figure 1). What are the implications of these important findings for the treatment of cancer in humans? ICB therapy is one of the most exciting medical breakthroughs in recent years, but it is limited by treatment resistance and toxicity. Now, we have a new understanding of why this may be and how a single, small molecule might act to stimulate and support anti-tumor T cell function and improve ICB response. We also have a better appreciation of how the composition and functional output of the gut microbiota may help to propel T cell-driven immunity. From a practical standpoint, should these mouse studies reflect human cancer immunobiology, inosine supplementation could be feasibly added to the diets of patients receiving ICB therapy. Alternatively, inosine-producing therapeutic microbes or consortia might represent a safe and efficacious way to deliver the molecule. It is important to note that the study by Mager et al. focuses on CTLA-4 inhibition, and its findings may not generalize to other modes of ICB (such as PD1/PDL1 inhibition). It is also likely, given the multiple and complex interactions between the gut microbiota and the host, that numerous mechanisms will be implicated in microbiome-mediated ICB responses, such as bacterial expression of tumor neoantigens (Bessell et al., 2020Bessell C.A. Isser A. Havel J.J. Lee S. Bell D.R. Hickey J.W. Chaisawangwong W. Glick Bieler J. Srivastava R. Kuo F. et al.Commensal bacteria stimulate antitumor responses via T cell cross-reactivity.JCI Insight. 2020; 5: e135597Crossref PubMed Scopus (16) Google Scholar). Finally, inosine is unlikely to overcome some modes of ICB resistance intrinsic to the tumor and independent of the microbiome. It is unsurprising that the microbiome is a rich source of metabolites that are intimately associated with our own human metabolism. Thanks to hundreds of millions of years of co-evolution, eukaryotic symbiosis with a pharmacopeia in the form of a microbiome is an efficient strategy for enhancing metabolism, physiology, and immunity. There are a staggering number of microbial genes within the human microbiome that have yet to be explored and functionally characterized in health, disease, and disease treatment. A recent study provides a catalog of over 200,000 collective reference genomes from the human gut alone, representative of over 4,600 separate species, and conservatively count over 70 million predicted proteins with no known database matches or with unknown functions (Almeida et al., 2020Almeida A. Nayfach S. Boland M. Strozzi F. Beracochea M. Shi Z.J. Pollard K.S. Sakharova E. Parks D.H. Hugenholtz P. et al.A unified catalog of 204,938 reference genomes from the human gut microbiome.Nat. Biotechnol. 2020; (Published online July 20, 2020)https://doi.org/10.1038/s41587-020-0603-3Crossref PubMed Scopus (64) Google Scholar). Therapeutically augmenting the human microbiome and complementing its function with microbially produced supplements is a target-rich approach for identifying novel therapies and adjuncts in human disease. As a growing number of studies show, detecting and pursuing these targets in cancer treatment may lead to new treatments or improved outcomes for current drugs. E.A.-V. is a co-founder and Chief Scientific Officer of NuBiyota LLC, a company that is working to create therapies based on the human gut microbiota for clinical use. B.C. receives in-kind research support from NuBiyota LLC.