癌症研究
CD8型
表皮生长因子受体
免疫疗法
封锁
表皮生长因子受体抑制剂
细胞毒性T细胞
肿瘤微环境
医学
肺癌
T细胞
免疫学
生物
免疫系统
癌症
受体
内科学
体外
生物化学
肿瘤细胞
作者
Kazuya Nishii,Kadoaki Ohashi,Shuta Tomida,Takamasa Nakasuka,Atsuko Hirabae,Sachi Okawa,Jun Nishimura,Hisao Higo,Hiromi Watanabe,Hirohisa Kano,Chihiro Ando,Go Makimoto,Kiichiro Ninomiya,Yuka Kato,Toshio Kubo,Eiki Ichihara,Katsuyuki Hotta,Masahiro Tabata,Shinichi Toyooka,Heiichiro Udono,Yoshinobu Maeda,Katsuyuki Kiura
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2022-07-08
卷期号:10 (9): 1111-1126
被引量:10
标识
DOI:10.1158/2326-6066.cir-21-0751
摘要
Epidermal growth factor receptor (EGFR) is the most frequently mutated driver oncogene in nonsmoking-related, non-small cell lung cancer (NSCLC). EGFR-mutant NSCLC has a noninflamed tumor microenvironment (TME), with low infiltration by CD8+ T cells and, thus, immune-checkpoint inhibitors, such as antiprogrammed cell death-1 (anti-PD-1), have weak antitumor effects. Here, we showed that CD8+ T-cell responses were induced by an EGFR-tyrosine kinase inhibitor (TKI) in syngeneic Egfr-mutant NSCLC tumors, which was further pronounced by the sequential dual blockade of PD-1 and vascular endothelial growth factor receptor 2 (VEGFR2). However, the simultaneous triple blockade had no such effect. The PD-1/VEGFR2 dual blockade did not exert tumor-inhibitory effects without pretreatment with the EGFR-TKI, suggesting that the treatment schedule is crucial for the efficacy of the dual blockade therapy. Pretreatment with EGFR-TKI increased the CD8+ T-cell/regulatory T-cell (Treg) ratio, while also increasing the expression of immunosuppressive chemokines and chemokine receptors, as well as increasing the number of M2-like macrophages, in the TME. Discontinuing EGFR-TKI treatment reversed the transient increase of immunosuppressive factors in the TME. The subsequent PD-1/VEGFR2 inhibition maintained increased numbers of infiltrating CD8+ T cells and CD11c+ dendritic cells. Depletion of CD8+ T cells in vivo abolished tumor growth inhibition by EGFR-TKI alone and the sequential triple therapy, suggesting that EGFR inhibition is a prerequisite for the induction of CD8+ T-cell responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with cancers that have driver mutations and a noninflamed TME.
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