Goc et al. investigated the role of ILC3s on CRC responsiveness to checkpoint blockade. Profiles of resected tumors from 72 patients and mouse CRC models revealed significantly decreased ILC3s compared to normal tissue and an elevated T:ILC3 cell ratio that favored TH17 and compromised TH1 immunity. In normal tissue, ILC3:T cell interactions via MHC II supported specific microbiota colonization and a TH1 response; mice lacking MHC II in ILC3 cells exhibited microbiome changes and resistance to anti-PD-1, and progressed to CRC. Microbiota from humans with altered ILC3s promoted resistance to anti-PD-1 when transplanted into tumor-bearing mice.
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medici
Author Info: (1) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. (2) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. (3) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. (4) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. (5) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. (6) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. (7) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. (8) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA. Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA. (9) Microenvironment and Immunity Unit, Institut Pasteur, Paris, France. (10) College of Medical and Dental Sciences, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK. (11) Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. (12) Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA; Gastrointestinal Oncology Program, Center for Advanced Digestive Care, Sandra and Edward Meyer Cancer Center, New York-Presbyterian Hospital, Weill Cornell Medicine, Cornell University, New York, NY, USA. (13) Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA; Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology and Hepatology, Weill Cornell Medicine, Cornell University, New York, NY, USA; Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. Electronic address: gfsonnenberg@med.cornell.edu.
