Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer.

TitleDysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer.
Publication TypeJournal Article
Year of Publication2021
AuthorsGoc, J, Lv, M, Bessman, NJ, Flamar, A-L, Sahota, S, Suzuki, H, Teng, F, Putzel, GG, Eberl, G, Withers, DR, Arthur, JC, Shah, MA, Sonnenberg, GF
Corporate AuthorsJRI Live Cell Bank
JournalCell
Volume184
Issue19
Pagination5015-5030.e16
Date Published2021 Sep 16
ISSN1097-4172
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.

DOI10.1016/j.cell.2021.07.029
Alternate JournalCell
PubMed ID34407392
PubMed Central IDPMC8454863
Grant ListR01 DK124617 / DK / NIDDK NIH HHS / United States
R01 AI162936 / AI / NIAID NIH HHS / United States
R21 CA249274 / CA / NCI NIH HHS / United States
R01 AI123368 / AI / NIAID NIH HHS / United States
F32 AI124517 / AI / NIAID NIH HHS / United States
R01 AI143842 / AI / NIAID NIH HHS / United States
U01 AI095608 / AI / NIAID NIH HHS / United States
R01 AI145989 / AI / NIAID NIH HHS / United States
K01 DK103952 / DK / NIDDK NIH HHS / United States