NKG2D signaling regulates IL-17A-producing γδT cells in mice to promote cancer progression

Curio, S. et al. (2022) NKG2D signaling regulates IL-17A-producing γδT cells in mice to promote cancer progression. Discovery Immunology, 1(1), kyac002. (doi: 10.1093/discim/kyac002) (PMID:36277678) (PMCID:PMC9580227)

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γδT cells are unconventional T cells particularly abundant in mucosal tissues that play an important role in tissue surveillance, homeostasis and cancer. γδT cells recognize stressed cells or cancer cells through the NKG2D receptor to kill these cells and maintain normality. Contrary to the well-established anti-tumor function of these NKG2D-expressing γδT cells, we show here that, in mice, NKG2D regulates a population of pro-tumor γδT cells capable of producing IL-17A. Germline deletion of Klrk1, the gene encoding NKG2D, reduced the frequency of γδT cells in the tumor microenvironment and delayed tumor progression. We further show that blocking NKG2D reduced the capability of γδT cells to produce IL-17A in the pre-metastatic lung and that co-culture of lung T cells with NKG2D ligand-expressing tumor cells specifically increased the frequency of γδT cells. Together, these data support the hypothesis that in a tumor microenvironment where NKG2D ligands are constitutively expressed, γδT cells accumulate in an NKG2D-dependent manner and drive tumor progression by secreting pro-inflammatory cytokines, such as IL-17A.

Item Type:Articles
Additional Information:This work was supported by the Wellcome Trust RCDF (RCDF088381/Z/09/Z to N.G.), a Wellcome Trust PhD studentship (203948/Z/16A to S.C.), the Stevenson Fund to S.C., Breast Cancer Now (2018JulPR1101 to S.B.C.), Cancer Research UK Glasgow Centre (A25142 to S.B.C.), Wellcome Trust (208990/Z/17/Z to S.B.C.), Marie Curie European Fellowship (GDCOLCA 800112 to T.S.) and Naito Foundation Grant for Research Abroad (to T.S).
Glasgow Author(s) Enlighten ID:Wiesheu, Robert and Coffelt, Dr Seth and Glauner, Teresa and Edwards, Dr Sarah and Kilbey, Dr Anna
Authors: Curio, S., Edwards, S. C., Suzuki, T., McGovern, J., Triulzi, C., Yoshida, N., Jonsson, G., Glauner, T., Rami, D., Wiesheu, R., Kilbey, A., Purcell, R. V., Coffelt, S. B., and Guerra, N.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Discovery Immunology
Publisher:Oxford University Press
ISSN (Online):2754-2483
Published Online:10 May 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Discovery Immunology 1(1): kyac002
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
303457Regulation of IL-17-producing T cells in Breast Cancer MetastasisSeth CoffeltBreast Cancer Now (BRCANNOW)2018JulPR1101CS - Beatson Institute for Cancer Research
174115CRUK Centre RenewalOwen SansomCancer Research UK (CRUK)C7932/A25142CS - Beatson Institute for Cancer Research
301010understanding gamma delta T cell function in colorectal cancer metastasisSeth CoffeltWellcome Trust (WELLCOTR)208990/Z/17/ZCS - Beatson Institute for Cancer Research