| First Author | Naito Y | Year | 2023 |
| Journal | Sci Adv | Volume | 9 |
| Issue | 20 | Pages | eade0718 |
| PubMed ID | 37205755 | Mgi Jnum | J:335811 |
| Mgi Id | MGI:7485257 | Doi | 10.1126/sciadv.ade0718 |
| Citation | Naito Y, et al. (2023) Tumor-derived semaphorin 4A improves PD-1-blocking antibody efficacy by enhancing CD8(+) T cell cytotoxicity and proliferation. Sci Adv 9(20):eade0718 |
| abstractText | 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. |
