Liu, Xu, and Zhang et al. showed that tumor cell-derived SDC1(Syndecan-1) inhibits CD8+ T cell infiltration and activation in the tumor microenvironment. SDC1 ablation in the tumor cells enhanced IFNγ–STAT1 signaling, augmented MHC-I expression, and sensitized tumors to T cell-mediated cytotoxicity. SDC1 deficiency sensitized MC38 tumors to PD-1 blockade, and B16 tumors to GVAX and PD-1 blockade, leading to a robust antitumor immune response. Lower SDC1 expression correlated with better prognosis in patients with glioblastoma, melanoma, and renal cell carcinoma who were treated with ICB.
Contributed by Shishir Pant
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-_-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.
Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China. (2) Sta
Author Info: (1) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China. (2) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China. (3) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China. (4) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China. (5) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China. (6) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China. (7) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China. (8) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China. (9) Affiliated Cancer Hospital and Institute, Guangzhou Medical University, Guangzhou, China. (10) State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
