| Author |
Naito Y, Koyama S, Masuhiro K, Hirai T, Uenami T, Inoue T, Osa A, Machiyama H, Watanabe G, Sax N, Villa J, Kinugasa-Katayama Y, Nojima S, Yaga M, Hosono Y, Okuzaki D, Satoh S, Tsuda T, Nakanishi Y, Suga Y, Morita T, Fukushima K, Nishide M, Shiroyama T, Miyake K, Iwahori K, Hirata H, Nagatomo I, Yano Y, Tamiya M, Kumagai T, Takemoto N, Inohara H, Yamasaki S, Yamashita K, Aoshi T, Akbay EA, Hosen N, Shintani Y, Takamatsu H, Mori M, Takeda Y, Kumanogoh A.
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| Abstract |
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.
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