State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
Affiliated Cancer Hospital and Institute, Guangzhou Medical University, Guangzhou, China.
Sci Adv. 2024 Sep 13;10(37):eadi7764. doi: 10.1126/sciadv.adi7764. Epub 2024 Sep 11.
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 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.
肿瘤细胞起源的事件会阻止有效的抗肿瘤免疫反应，并限制抗 PD1 检查点免疫疗法的应用。我们表明， syndecan-1（SDC1）在调节 T 细胞介导的肿瘤生长控制中具有关键作用。SDC1 抑制增加了 CD8 T 细胞进入肿瘤的渗透，并触发 CD8 T 细胞介导的肿瘤生长控制，同时增加了祖细胞耗竭和效应样 CD8 T 细胞的比例。SDC1 缺乏改变了肿瘤细胞中的多种信号事件，包括增强 IFN-γ-STAT1 信号，以及增强抗原呈递和对 T 细胞介导的细胞毒性的敏感性。SDC1 的联合抑制显著增强了抗 PD1 抑制肿瘤生长的治疗效果。一致地，来自人类肿瘤的数据支持了这些发现，表明表达与肿瘤组织中 T 细胞的存在呈负相关，与免疫检查点阻断治疗的反应相关。我们的发现表明 SDC1 抑制抗肿瘤免疫，而靶向 SDC1 可能促进抗 PD1 反应以用于癌症治疗。
