调节性 T 细胞对肝转移全身免疫和免疫治疗反应的控制。
Regulatory T cell control of systemic immunity and immunotherapy response in liver metastasis.
机构信息
Division of Hematology and Oncology, University of California, San Francisco, San Francisco, CA 94143, USA.
Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA 94143, USA.
出版信息
Sci Immunol. 2020 Oct 2;5(52). doi: 10.1126/sciimmunol.aba0759.
Abstract
Patients with cancer with liver metastasis demonstrate significantly worse outcomes than those without liver metastasis when treated with anti-PD-1 immunotherapy. The mechanism of liver metastases-induced reduction in systemic antitumor immunity is unclear. Using a dual-tumor immunocompetent mouse model, we found that the immune response to tumor antigen presence within the liver led to the systemic suppression of antitumor immunity. The immune suppression was antigen specific and associated with the coordinated activation of regulatory T cells (T) and modulation of intratumoral CD11b monocytes. The dysfunctional immune state could not be reversed by anti-PD-1 monotherapy unless T cells were depleted (anti-CTLA-4) or destabilized (EZH2 inhibitor). Thus, this study provides a mechanistic understanding and rationale for adding T and CD11b monocyte targeting agents in combination with anti-PD-1 to treat patients with cancer with liver metastasis.
摘要
患有肝转移的癌症患者在接受抗 PD-1 免疫治疗时，其预后明显比没有肝转移的患者差。肝转移导致全身性抗肿瘤免疫降低的机制尚不清楚。本研究使用双重肿瘤免疫活性小鼠模型发现，肝脏内存在肿瘤抗原所引起的免疫反应会导致全身性抗肿瘤免疫抑制。这种免疫抑制具有抗原特异性，并与调节性 T 细胞（T 细胞）的协调激活和肿瘤内 CD11b 单核细胞的调节有关。除非耗尽 T 细胞（抗 CTLA-4）或使 T 细胞失稳（EZH2 抑制剂），否则抗 PD-1 单药治疗无法逆转这种功能失调的免疫状态。因此，这项研究为联合抗 PD-1 治疗肝转移癌症患者时添加 T 细胞和 CD11b 单核细胞靶向药物提供了机制理解和理论依据。
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