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

• DOI: 10.1158/2326-6066.c.6551013
• Publication Date: 2023-04-04T18:31:25Z
• Authors: Fernando Souza-Fo...; 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. Hunti...
• Keywords: Interleukin 15; Immunosurveillance; Cancer Immunotherapy

<div>Abstract<p>Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8<sup>+</sup> T cells. Interest in analogous pathways other lymphocytes is growing. Natural killer (NK) cells are key to immunosurveillance eradicating metastases and driving solid tumor inflammation. NK-cell antitumor function dependent on the cytokine IL15. Ablation of IL15 signaling inhibitor CIS (<i>Cish</i>) enhances immunity increasing metabolism persistence within microenvironment (TME). The TME has also been shown impair fitness via production immunosuppressive transforming growth factor β (TGFβ), a suppression which occurs even presence high signaling. Here, we identified an unexpected interaction between TGFβ pathway NK Independently, <i>Cish</i>- <i>Tgfbr2</i>-deficient both hyperresponsive hyporesponsive TGFβ, with dramatically enhanced immunity. Remarkably, when these genes simultaneously deleted cells, mice largely resistant development, suggesting that combining two might represent novel therapeutic strategy enhance innate anticancer immunity.</p></div>