Syndecan-1 inhibition promotes antitumor immune response and facilitates the efficacy of anti-PD1 checkpoint immunotherapy
Yun Liu, Chen Xu, Li Zhang, Guiqin Xu, Zhaojuan Yang, Lvzhu Xiang, Kun Jiao, Zehong Chen, Xiaoren Zhang, Yongzhong Liu
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.