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

Fernando Souza-Fonseca-Guimaraes, Gustavo R. Rossi, Laura F. Dagley, Momeneh Foroutan, Timothy R. McCulloch, Jumana Yousef, Hae-Young Park, Jennifer H. Gunter, Paul A. Beavis, Cheng-Yu Lin, Soroor Hediyeh-Zadeh, Tania Camilleri, Melissa J. Davis, Nicholas D. Huntington

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 anti-tumor function is dependent on the cytokine interleukin (IL)-15. Ablation of the IL-15 signaling inhibitor CIS (Cish) enhances NK cell anti-tumor 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 TGF-β, a suppression which occurs even in the presence of high IL-15 signaling. Here, we identified an unexpected interaction between CIS and the TGF-β signaling pathway in NK cells. Independently, Cish- and Tgfbr2-deficient NK cells are both hyper-responsive to IL-15 and hypo-responsive to TGF-β, with dramatically enhanced anti-tumor 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 anti-cancer immunity.