A novel role for Cish in the inhibition of TCR signaling

Cancer immunotherapeutics focus primarily on stimulating the immune system to elicit endogenous immune responses to fight cancer or transferring primed immune effectors in adoptive cell transfer (ACT) paradigms (1,2). CD8⁺ T cells are desirable immune effectors in cancer, however, their antitumor activity is often attenuated by tolerance mechanisms or the suppressive nature of the tumor microenvironment (3). As such, the goal of cancer immunotherapies is increasingly focusing on overcoming the tumor tolerance barrier by enhancing the antigen reactivity and effector function of tumor-specific T cells (4), however, the presence of T cells with high-affinity for their cognate antigen is often precluded by thymic selection (5,6). Therefore, developing methods of enhancing T cell receptor (TCR) signaling or functional avidity to maximize antitumor efficacy of tumor-specific T cells (7) can improve cancer therapies employing ACT, vaccines, or checkpoint inhibitors. Current approaches include the development of affinity-enhanced antigen receptors for ACT therapies, but these have been met with challenges (8,9), including treatment-related toxicities (10-12). In an effort to identify new druggable targets to increase CD8+ T cell functional avidity for tumor-specific antigens and increase tumor killing, Palmer et al. identified a novel intrinsic pathway inhibiting TCR signaling cascades and limiting CD8+ T cell activity in murine tumors (13).