TGFbeta and CIS Inhibition Overcomes NK-cell Suppression to Restore Antitumor Immunity
- Author(s)
- Souza-Fonseca-Guimaraes, F; Rossi, GR; Dagley, LF; Foroutan, M; McCulloch, TR; Yousef, J; Park, HY; Gunter, JH; Beavis, PA; Lin, CY; Hediyeh-Zadeh, S; Camilleri, T; Davis, MJ; Huntington, ND;
- Details
- Publication Year 2022-09-01,Volume 10,Issue #9,Page 1047-1054
- Journal Title
- Cancer Immunology Research
- Publication Type
- Research article
- 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 transforming growth factor beta (TGFbeta), a suppression which occurs even in the presence of high IL15 signaling. Here, we identified an unexpected interaction between CIS and the TGFbeta signaling pathway in NK cells. Independently, Cish- and Tgfbr2-deficient NK cells are both hyperresponsive to IL15 and hyporesponsive to TGFbeta, 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.
- Keywords
- Animals; Cell Line, Tumor; *Interleukin-15/metabolism; Killer Cells, Natural; Mice; *Neoplasms/pathology; Transforming Growth Factor beta/metabolism; Tumor Microenvironment
- Department(s)
- Laboratory Research
- PubMed ID
- 35759796
- Publisher's Version
- https://doi.org/10.1158/2326-6066.CIR-21-1052
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-04-11 03:02:40
Last Modified: 2025-04-11 03:05:16