Targeting the immunoglobulin IGSF9 enhances anti-tumor T cell activity and sensitivity to anti-PD-1 immunotherapy

Immune checkpoints modulate the immune response and represent important immunotherapy targets for cancer treatment. However, as many tumors are resistant to current immune checkpoint inhibitors, the discovery of novel immune checkpoints could facilitate the development of additional immunotherapeutic strategies to improve patient responses. Here, we identified increased expression of the adhesion molecule immunoglobulin superfamily member 9 (IGSF9) in tumor cells and tumor-infiltrating immune cells across multiple cancer types. IGSF9 overexpression or knockout in tumor cells did not alter cell proliferation in vitro or tumor growth in immunocompromised mice. Alternatively, IGSF9 deficient tumor cells lost the ability to suppress T cell proliferation and exhibited reduced growth in immunocompetent mice. Similarly, growth of tumor cells was reduced in IGSF9 knockout syngeneic and humanized mice, accompanied by increased tumor-infiltrating T cells. Mechanistically, the extracellular domain (ECD) of IGSF9 bound to T cells and inhibited their proliferation and activation, and the tumor promoting effect of IGSF9 ECD was reversed by CD3+ T cell depletion. Anti-IGSF9 antibody treatment inhibited tumor growth and enhanced the anti-tumor efficacy of anti-PD-1 immunotherapy. Single-cell RNA sequencing revealed tumor microenvironment remodeling from tumor-promoting to tumor-suppressive following anti-IGSF9 treatment. Together, these results indicate that IGSF9 promotes tumor immune evasion and is a candidate immune checkpoint target.

免疫检查点（immune checkpoints）可调控免疫应答，是癌症治疗中重要的免疫治疗靶点。然而，多数肿瘤对当前的免疫检查点抑制剂（immune checkpoint inhibitors）存在耐药性，因此发现新型免疫检查点有助于开发更多免疫治疗策略，以改善患者的治疗响应。本研究在多种癌症类型的肿瘤细胞及肿瘤浸润免疫细胞中，检测到黏附分子免疫球蛋白超家族成员9（IGSF9）的表达上调。在肿瘤细胞中过表达或敲除IGSF9，均未改变体外细胞增殖能力，也未影响免疫缺陷小鼠体内的肿瘤生长。与之相反，IGSF9缺陷的肿瘤细胞丧失了抑制T细胞增殖的能力，且在免疫健全小鼠体内的生长能力显著减弱。同样，在IGSF9敲除的同基因小鼠与人源化小鼠中，肿瘤细胞的生长均受到抑制，同时肿瘤浸润T细胞数量增加。机制研究显示，IGSF9的细胞外结构域（ECD）可结合T细胞并抑制其增殖与活化，而CD3阳性T细胞耗竭可逆转IGSF9 ECD的促肿瘤作用。抗IGSF9抗体治疗可抑制肿瘤生长，并增强抗PD-1免疫治疗的抗肿瘤效能。单细胞RNA测序（single-cell RNA sequencing）结果表明，抗IGSF9治疗后，肿瘤微环境（tumor microenvironment）从促肿瘤表型重塑为抑肿瘤表型。综上，上述结果证实IGSF9可促进肿瘤免疫逃逸（tumor immune evasion），是一款潜在的免疫检查点治疗靶点。