Journal article
TGFβ and CIS Inhibition Overcomes NK-cell Suppression to Restore Antitumor Immunity
F Souza-Fonseca-Guimaraes, GR Rossi, LF Dagley, M Foroutan, TR McCulloch, J Yousef, HY Park, JH Gunter, PA Beavis, CY Lin, S Hediyeh-Zadeh, T Camilleri, MJ Davis, ND Huntington
Cancer Immunology Research | Published : 2022
Abstract
Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8+ T cells. Interest in targeting analogous pathways in other cytotoxic lymphocytes is growing. Natural killer (NK) cells are key to cancer immunosurveillance by eradicating metastases and driving solid tumor inflammation. NK-cell antitumor function is dependent on the cytokine IL15. Ablation of the IL15 signaling inhibitor CIS (Cish) enhances NK-cell antitumor immunity by increasing NK-cell metabolism and persistence within the tumor microenvironment (TME). The TME has also been shown to impair NK-cell fitness via the production of immunosuppressive ..
View full abstractGrants
Awarded by U.S. Department of Defense
Funding Acknowledgements
This work is supported by project grants from the National Health and Medical Research Council (NHMRC) of Australia (#1140406, to F. Souza-Fonseca-Guimaraes; #115995, to N.D. Huntington) . N.D. Huntington is supported by NHMRC Ideas Grant #118461 and Investigator Fellowship #119529. F. Souza-Fonseca-Guimaraes is funded by a UQ Diamantina Institute Laboratory Start-Up Package, a U.S. Department of Defense-Breast Cancer Research Program- Breakthrough Award Level 1 (#BC200025) , a grant (1158085) awarded through the Priority-driven Collaborative Cancer Research Scheme and co-funded by Cancer Australia and Cure Cancer, and a ANZSA Sarcoma Research Grant (supported by Kicking Goals for Xav, Stoney's Steps, and Stop Sarcoma) . We thank all the members of the Huntington and Guimaraes Laboratories, Dr. S. F. Ngiow, Prof. G. McArthur, and Prof. A. Yoshimura for discussion, comments, and advice on this project; Dr. G. E. Bollag (Plexxikon Inc) for providing PLX4720 for in vivo studies; Prof. S. Karlsson for providing the TgfbRII flox mice; Prof. E. Vivier for providing the NKp46cre mice; and Profs. J. Ihle and E. Parganas for providing the CIS knockout mice.