Refined Modulation of Natural Killer Cells by Transforming Growth Factor‐β Isoforms

Natural killer (NK) cells constitute the vital first line of defense against tumors and have demonstrated promising therapeutic efficacy in the treatment of multiple types of cancer. Meanwhile, the tumor microenvironment impedes anticancer activity, and transforming growth factor (TGF)-β is a key immunosuppressive cytokine. Indeed, TGF-β inhibition shows preclinical success but faces clinical challenges, and concurrently, the distinct functions of TGF-β isoforms have been increasingly recognized. We here elucidated the effects of TGF-β isoforms on NK cells, and a genome-wide analysis identified TGF-β3 as a regulator of gene expression distinct from TGF-β1 and TGF-β2. The top hit among the genes specifically upregulated by TGF-β3 was innate immunity activator (INAVA). INAVA elevated interferon gamma (IFN-γ) signaling, leading to increased IFN-γ release and NK cell cytotoxicity against cancer cells. In contrast to the pan-TGF-β antibody, our anti-TGF-β1 aptamer did not interfere with the upregulation of INAVA by TGF-β3. Finally, clinical data analyses demonstrated that the expression of INAVA was correlated with activated tumor-infiltrating NK (TINK) cells and survival in patients with melanoma, a leading TINK cell-targeted cancer. Thus, a new unique action of TGF-β3 indicates an immunobiologically sophisticated control of NK cells by TGF-β isoforms and the immunotherapeutic importance of their selective modulation.