Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer

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. [Display omitted] •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 ILC3s are altered in the tumor microenvironment of humans with colorectal cancer, resembling those found in the inflamed intestine. In mice, ILC3s regulate adaptive immunity, shape the microbiota composition, and protect from tumor progression as well as colorectal cancer immunotherapy resistance.