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

Menée à l'aide de lignées cellulaires, de modèles murins et d'échantillons tumoraux issus de patients atteints d'un cancer du poumon non à petites cellules, cette étude démontre que la sémaphorine 4A synthétisée par les cellules cancéreuses améliore l'efficacité des anti-PD1 en augmentant la prolifération et la cytotoxicité des lymphocytes T CD8+

Résumé en anglais

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. Sema4A increases sensitivity to PD-1–blocking therapy by enhancing co-stimulation of CD8+ T cells in the tumor microenvironment.