CD8型
启动(农业)
肿瘤微环境
癌症研究
免疫疗法
肿瘤抗原
免疫学
免疫系统
树突状细胞
细胞毒性T细胞
医学
生物
兴奋剂
癌症免疫疗法
免疫检查点
过继性细胞移植
癌症
T细胞
化学
封锁
刺
细胞因子
抗原
生物化学
体外
发芽
植物
作者
Jeremy B. Foote,Marleen Kok,James M. Leatherman,Todd D. Armstrong,Bridget C. Marcinkowski,Laureen S. Ojalvo,David B. Kanne,Elizabeth M. Jaffee,Thomas W. Dubensky,Leisha A. Emens
出处
期刊:Cancer immunology research
[American Association for Cancer Research]
日期:2017-06-01
卷期号:5 (6): 468-479
被引量:114
标识
DOI:10.1158/2326-6066.cir-16-0284
摘要
Abstract Stimulator of interferon genes (STING) signaling induces IFNβ production by intratumoral dendritic cells (DC), driving T-cell priming and recruitment into the tumor microenvironment (TME). We examined to what extent preexisting antigen-specific tolerance influenced the efficacy of in situ delivery of a potent STING-activating cyclic dinucleotide (CDN), ADU S-100, against established HER-2+ breast tumors. ADU S-100 induced HER-2–specific CD8+ T-cell priming and durable tumor clearance in 100% of nontolerant parental FVB/N mice. In contrast, ADU S-100 did not sufficiently prime HER-2–specific CD8+ T cells in tolerant neu/N mice, resulting in only delayed tumor growth and tumor clearance in 10% of the mice. No differences in IFNβ production, DC priming, or HER-2–specific CD8+ T-cell trafficking were detected between FVB/N and neu/N mice. However, activation and expansion of HER-2–specific CD8+ T cells were defective in neu/N mice. Immune cell infiltrates of untreated tumor-bearing neu/N mice expressed high numbers of PD1 and OX40 receptors on their CD8+ T cells, and PD-L1 was highly expressed on both myeloid and tumor cells. Modulating PD-L1 and OX40 receptor signaling combined with intratumoral ADU S-100 administration enhanced HER-2–specific CD8+ T-cell activity, clearing tumors in 40% of neu/N mice. Thus, intratumoral STING agonists could potently prime tumor antigen–specific CD8+ T-cell responses, and adding PD-L1 blockade and OX40 receptor activation can overcome antigen-enforced immune tolerance to induce tumor regression. Cancer Immunol Res; 5(6); 468–79. ©2017 AACR.
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