摘要
•Profiling of human and mouse CRC reveals a substantial dysregulation of ILC3s•ILC3 and T cell interactions support microbiota that drives type-1 immunity•ILC3 impairment drives CRC progression and immunotherapy resistance in mice•Humans with altered ILC3s harbor microbiota that causes immunotherapy resistance Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance. Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance. Interactions between mammals and microbes profoundly impact cancer (Dzutsev et al., 2017Dzutsev A. Badger J.H. Perez-Chanona E. Roy S. Salcedo R. Smith C.K. Trinchieri G. Microbes and Cancer.Annu. Rev. 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Duong C.P.M. et al.Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.Science. 2015; 350: 1079-1084Crossref PubMed Scopus (1727) Google Scholar; Sivan et al., 2015Sivan A. Corrales L. Hubert N. Williams J.B. Aquino-Michaels K. Earley Z.M. Benyamin F.W. Lei Y.M. Jabri B. Alegre M.-L. et al.Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy.Science. 2015; 350: 1084-1089Crossref PubMed Scopus (1877) Google Scholar; Gopalakrishnan et al., 2018Gopalakrishnan V. Spencer C.N. Nezi L. Reuben A. Andrews M.C. Karpinets T.V. Prieto P.A. Vicente D. Hoffman K. Wei S.C. et al.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.Science. 2018; 359: 97-103Crossref PubMed Scopus (1932) Google Scholar; 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 (1240) Google Scholar; Routy et al., 2018bRouty 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 (2269) Google Scholar; Tanoue et al., 2019Tanoue T. Morita S. Plichta D.R. Skelly A.N. Suda W. Sugiura Y. Narushima S. Vlamakis H. Motoo I. Sugita K. et al.A defined commensal consortium elicits CD8 T cells and anti-cancer immunity.Nature. 2019; 565: 600-605Crossref PubMed Scopus (434) Google Scholar). Moreover, recent studies demonstrated that fecal microbiota transplantation (FMT) may be harnessed as a method to boost responsiveness to checkpoint blockade in resistant cancer patients (Baruch et al., 2021Baruch E.N. Youngster I. 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