Sushi domain containing 2 suppresses CD8+ T cell antitumor immunity by targeting IL-2 receptor signaling

Abstract

Abstract One major mechanism of immunosuppressive tumor microenvironment (TME) is dysfunctional CD8+ T cells which exhibit defective production of antitumor effector molecules. However, the intrinsic molecular mechanism(s) underlying CD8+ T cell dysfunction in cancer remains incompletely understood. Here, we show that the sushi domain containing 2 (SUSD2) is a negative regulator of CD8+ T cell antitumor function. Genetic deletion of Susd2 (Susd2−/−) results in an enhanced production of antitumor molecules in effector CD8+ T cells, which consequently blunts tumor growth in multiple syngeneic mouse tumor models. Through a quantitative mass spectrometry assay, we find that SUSD2 interacts with interleukin-2 receptor a (IL-2Ra) via sushi domain-dependent protein interaction and their interaction suppresses IL-2Ra binding with IL-2, a well-established cytokine essential for CD8+ T cell effector function. Adoptive transfer of Susd2−/− CD19-targeting chimeric antigen receptor (CAR) T cells induces a robust antitumor effect, highlighting SUSD2 as a potential immunotherapy target for cancer treatment. Supported by grants from NIH (R01 AI62779-01)