Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Department of Immunology and Molecular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Sci Adv. 2023 May 19;9(20):eade0718. doi: 10.1126/sciadv.ade0718.
Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non-small cell lung cancer (NSCLC) responded significantly better to anti-programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8 T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy.
免疫检查点抑制剂（ICIs）在癌症治疗方面带来了革命性的变化，但低反应率仍是一个挑战。信号素 4A（Sema4A）在小鼠中通过多种机制来调节免疫系统，尽管人类 Sema4A 在肿瘤微环境中的作用仍不清楚。本研究表明，组织学上 Sema4A 阳性的非小细胞肺癌（NSCLC）对抗程序性细胞死亡蛋白 1（PD-1）抗体的反应明显优于 Sema4A 阴性的 NSCLC。有趣的是，人类 NSCLC 中的 SEMA4A 表达主要来源于肿瘤细胞，并与 T 细胞激活有关。Sema4A 通过增强雷帕霉素复合物 1 和多胺合成来促进肿瘤特异性 CD8 T 细胞的细胞毒性和增殖，而不会导致其终末耗竭，从而提高了 PD-1 抑制剂在小鼠模型中的疗效。使用来自癌症患者的分离的肿瘤浸润性 T 细胞也证实了重组 Sema4A 对 T 细胞激活的改善作用。因此，Sema4A 可能是一种有前途的治疗靶点和预测及促进 ICI 疗效的生物标志物。
