AbstractImmune 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.はじめに免疫チェックポイント阻害薬（ICI）は，様々ながん種に対する治療において大きな革新をもたらした．しかし，ICI が臨床的に有効な患者は限定されている．また，治療効果を予測する BM として大阪大学医学系研究科呼吸器・免疫内科学教室・助教Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University内藤 祐二朗Yujiro Naito― 159 ―免疫セマフォリンを標的としたがん免疫療法の新規バイオマーカー及び新規免疫複合療法の開発Development of novel biomarkers and therapies for cancer immunotherapy targeting immune semaphorins
元のページ ../index.html#161