Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8+T cell cytotoxicity and proliferation

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 mecha-nisms 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 signifi-cantly 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 acti-vation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8+T cells without terminal exhaus-tion 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 con-firmed 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.

Automated summary

The expression of Sema4A in tumor cells of non-small cell lung cancer is associated with a better response to PD-1 inhibitors. Sema4A enhances the cytotoxicity and proliferation of tumor-specific CD8+ T cells and improves the efficacy of PD-1 inhibitors. Therefore, Sema4A may serve as a promising therapeutic target and biomarker for predicting and promoting immune checkpoint inhibitor efficacy.