Syndecan-1 inhibition promotes antitumor immune response and facilitates the efficacy of anti-PD1 checkpoint immunotherapy

Abstract

Tumor cell–originated events prevent efficient antitumor immune response and limit the application of anti-PD1 checkpoint immunotherapy. We show that syndecan-1 (SDC1) has a critical role in the regulation of T cell–mediated control of tumor growth. SDC1 inhibition increases the permeation of CD8 + T cells into tumors and triggers CD8 + T cell–mediated control of tumor growth, accompanied by increased proportions of progenitor-exhausted and effector-like CD8 + T cells. SDC1 deficiency alters multiple signaling events in tumor cells, including enhanced IFN-γ–STAT1 signaling, and augments antigen presentation and sensitivity to T cell–mediated cytotoxicity. Combinatory inhibition of SDC1 markedly potentiates the therapeutic effects of anti-PD1 in inhibiting tumor growth. Consistently, the findings are supported by the data from human tumors showing that SDC1 expression negatively correlates with T cell presence in tumor tissues and the response to immune checkpoint blockade therapy. Our findings suggest that SDC1 inhibits antitumor immunity, and that targeting SDC1 may promote anti-PD1 response for cancer treatment.