Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer

Cell. 2021 Sep 16;184(19):5015-5030.e16. doi: 10.1016/j.cell.2021.07.029. Epub 2021 Aug 17.


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.

Keywords: checkpoint blockade immunotherapy; colorectal cancer; innate lymphoid cells; intestinal inflammation; microbiota.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Communication / drug effects
  • Cell Plasticity / drug effects
  • Colonic Neoplasms / immunology*
  • Colonic Neoplasms / microbiology
  • Colonic Neoplasms / therapy*
  • Disease Progression*
  • Feces / microbiology
  • Histocompatibility Antigens Class II / metabolism
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immunity, Innate* / drug effects
  • Immunotherapy*
  • Inflammation / immunology
  • Inflammation / pathology
  • Inflammatory Bowel Diseases / immunology
  • Inflammatory Bowel Diseases / microbiology
  • Inflammatory Bowel Diseases / pathology
  • Intestines / pathology
  • Lymphocytes / drug effects
  • Lymphocytes / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Microbiota / drug effects
  • Neoplasm Invasiveness
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • Tissue Donors


  • Histocompatibility Antigens Class II
  • Immune Checkpoint Inhibitors