TGFβ and CIS Inhibition Overcomes NK-cell Suppression to Restore Antitumor Immunity.

Autor:	Souza-Fonseca-Guimaraes F; University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia., Rossi GR; University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia., Dagley LF; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Advanced Technology & Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Foroutan M; Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia., McCulloch TR; University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia., Yousef J; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Advanced Technology & Biology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Park HY; Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia., Gunter JH; Australian Prostate Cancer Research Centre - QLD, Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland University of Technology, Brisbane, Australia., Beavis PA; Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.; Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia., Lin CY; University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia., Hediyeh-Zadeh S; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Australian Prostate Cancer Research Centre - QLD, Centre for Genomics and Personalised Health, School of Biomedical Science, Queensland University of Technology, Brisbane, Australia., Camilleri T; Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia., Davis MJ; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.; Division of Bioinformatics, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia., Huntington ND; Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2022 Sep 01; Vol. 10 (9), pp. 1047-1054.
DOI:	10.1158/2326-6066.CIR-21-1052
Abstrakt:	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 transforming growth factor β (TGFβ), a suppression which occurs even in the presence of high IL15 signaling. Here, we identified an unexpected interaction between CIS and the TGFβ signaling pathway in NK cells. Independently, Cish- and Tgfbr2-deficient NK cells are both hyperresponsive to IL15 and hyporesponsive to TGFβ, with dramatically enhanced antitumor immunity. Remarkably, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development, suggesting that combining suppression of these two pathways might represent a novel therapeutic strategy to enhance innate anticancer immunity. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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