Immune checkpoint inhibitors (ICIs) are indicated for a diverse range of cancer types, and characterizing the tumor immune microenvironment is critical for optimizing therapeutic strategies, including ICIs. T cell infiltration and activation status in the tumor microenvironment greatly affects the efficacy of ICIs. Here, we show that semaphorin 6D (Sema6D) forward signaling, which is reportedly involved in coordinating the orientation of cell development and migration as a guidance factor, impaired the infiltration and activation of tumor-specific CD8+ T cells in murine oral tumors. Sema6D expressed by nonhematopoietic cells was responsible for this phenotype. Plexin-A4, a receptor for Sema6D, inhibited T cell infiltration and partially suppressed CD8+ T cell activation and proliferation induced by Sema6D stimulation. Moreover, mouse oral tumors, which are resistant to PD-1–blocking treatment in wild-type mice, showed a response to the treatment in Sema6d-KO mice. Finally, analyses of public data sets of human head and neck squamous cell carcinoma, pan-cancer cohorts, and a retrospective cohort study showed that SEMA6D was mainly expressed by nonhematopoietic cells such as cancer cells, and SEMA6D expression was significantly negatively correlated with CD8A, PDCD1, IFNG, and GZMB expression. Thus, targeting Sema6D forward signaling is a promising option for increasing ICI efficacy.
Takashi Hirai, Yujiro Naito, Shohei Koyama, Yoshimitsu Nakanishi, Kentaro Masuhiro, Mayuko Izumi, Tomoki Kuge, Maiko Naito, Yumiko Mizuno, Yuta Yamaguchi, Sujin Kang, Moto Yaga, Yu Futami, Satoshi Nojima, Masayuki Nishide, Takayoshi Morita, Yasuhiro Kato, Takeshi Tsuda, Norihiko Takemoto, Yumi Kinugasa-Katayama, Taiki Aoshi, Jordan Kelly Villa, Kazuo Yamashita, Tomohiro Enokida, Yuta Hoshi, Kazuto Matsuura, Makoto Tahara, Hyota Takamatsu, Yoshito Takeda, Hidenori Inohara, Atsushi Kumanogoh