TGF-β and CIS inhibition synergistically enhance natural killer cell-based immunity

Abstract

Abstract Immune “checkpoint” inhibitor antibodies have revolutionized cancer therapy and function by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8 T cells. Recent studies have also shown similar programs in other effector lymphocyte populations such as natural killer (NK) cells. NK cells are key to cancer immunosurveillance, particularly in settings of metastasis. They are dependent on the cytokine IL-15 for their survival, development, and function, with ablation of the IL-15 signaling inhibitor CIS (Cish), shown to enhance NK cell anti-tumor immunity by increasing NK cell fitness in the tumor microenvironment (TME). The TME has also been shown to impair NK cell fitness via the production of immunosuppressive transforming growth factor (TGF)-β, even in the presence of high IL-15 signaling. Here, taking advantage of sophisticated proteomics and transcriptomics methods with computational biology analysis we identified an unexpected interaction between CIS and the TGF-β signaling pathway in NK cells. Independently, for the first time a Cish- and Tgfbr2-double-deficient NK cells were generated by our group, which displayed both hyper-responsiveness to IL-15 and hypo-responsiveness to TGF-β, with dramatically enhanced immunity against multiple mouse models of cancer. Remarkable, when both these immunosuppressive genes are simultaneously deleted in NK cells, mice are largely resistant to tumor development and this resistance is dependent on NK cell hyper-activity. This study contributes to the understanding on how targeting multiple suppressive pathways unveils a new immunotherapy approach that might have broad therapeutic interventions, particularly by enhancing NK cell effector functions during disease. This work is supported by project grants from the National Health and Medical Research Council (NHMRC) of Australia (#1140406), the US Department of Defense – Breast Cancer Research Program – Breakthrough Award Level 1 (#BC200025), the ANZSA SRG Grant, and was supported by a grant (#1158085) awarded through the Priority-driven Collaborative Cancer Research Scheme and co-funded by Cancer Australia and Cure Cancer.