Hypoxia-Induced VISTA Promotes the Suppressive Function of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment
Hypoxia-Induced VISTA Promotes the Suppressive Function of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment
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DOI：
10.1158/2326-6066.cir-18-0507
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发表时间：
2019-07-01
影响因子：
10.1
通讯作者：
Mabaera, Rodwell
中科院分区：
文献类型：
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作者：
Deng, Jie;Li, Jiannan;Mabaera, Rodwell
肿瘤缺氧是一个与肿瘤信号激活、免疫逃逸和治疗抵抗有关的不良预后因素。确定缺氧在免疫逃逸和免疫检查点抑制剂抵抗中的机制作用可能有助于确定治疗靶点。我们和其他人已经证明，V-domain Ig suppressor of T-cell activation （VISTA）是B7家族中的一个负检查点调节因子，在肿瘤模型和原发性人类癌症的肿瘤微环境中高度表达。在这项研究中，我们发现VISTA和HIF1 α活性在结直肠癌患者队列中是相关的。高VISTA表达与较差的总生存率相关。我们采用CT26结肠癌模型，探讨缺氧对VISTA的调节作用。与低氧肿瘤区域或引流淋巴结相比，肿瘤微环境中深度缺氧区域与肿瘤浸润髓源性抑制细胞（MDSC）中VISTA表达增加有关。通过染色质免疫沉淀和基因沉默，我们发现缺氧诱导因子(HIF)-1 α与VISTA启动子中保守的缺氧反应元件结合可上调髓细胞上的VISTA。此外，在缺氧条件下，抗体靶向或基因消融VISTA可缓解MDSC介导的t细胞抑制，揭示VISTA是MDSC功能的中介。总的来说，这些数据表明，靶向VISTA可能会减轻缺氧对抗肿瘤免疫的有害影响。
Tumor hypoxia is a negative prognostic factor that is implicated in oncogenic signal activation, immune escape, and resistance to treatment. Identifying the mechanistic role of hypoxia in immune escape and resistance to immune-checkpoint inhibitors may aid the identification of therapeutic targets. We and others have shown that V-domain Ig suppressor of T-cell activation (VISTA), a negative checkpoint regulator in the B7 family, is highly expressed in the tumor microenvironment in tumor models and primary human cancers. In this study, we show that VISTA and HIF1 alpha activity are correlated in a cohort of colorectal cancer patients. High VISTA expression was associated with worse overall survival. We used the CT26 colon cancer model to investigate the regulation of VISTA by hypoxia. Compared with less hypoxic tumor regions or draining lymph nodes, regions of profound hypoxia in the tumor microenvironment were associated with increased VISTA expression on tumor-infiltrating myeloid-derived suppressor cells (MDSC). Using chromatin immunoprecipitation and genetic silencing, we show that hypoxia-inducible factor (HIF)-1 alpha binding to a conserved hypoxia response element in the VISTA promoter upregulated VISTA on myeloid cells. Further, antibody targeting or genetic ablation of VISTA under hypoxia relieved MDSC-mediated T-cell suppression, revealing VISTA as a mediator of MDSC function. Collectively, these data suggest that targeting VISTA may mitigate the deleterious effects of hypoxia on antitumor immunity.