Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice
Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice
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DOI：
10.1172/jci67313
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发表时间：
2014-02-01
影响因子：
15.9
通讯作者：
Fu, Yang-Xin
中科院分区：
文献类型：
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作者：
Deng, Liufu;Liang, Hua;Fu, Yang-Xin
高剂量电离辐射（IR）导致肿瘤细胞直接死亡并增强肿瘤特异性免疫，从而增强局部和远处的肿瘤控制。不幸的是，局部复发往往发生在IR治疗后，表明IR诱导的反应不足以维持抗肿瘤免疫力。当PD-L1在慢性炎症组织和肿瘤中表达时，T细胞负调节因子程序性死亡配体1（PD-L1，也称为B7-H1）的治疗性阻断可以增强T细胞效应器功能。在这里，我们证明了PD-Li在IR后的肿瘤微环境中上调。抗PD-L1的施用通过细胞毒性T细胞依赖性机制增强了IR的功效。伴随着IR介导的肿瘤消退，我们观察到IR和抗PD-L1协同减少肿瘤浸润性髓源性抑制细胞（MDSC）的局部积累，其抑制T细胞并改变肿瘤免疫微环境。此外，用联合疗法活化细胞毒性T细胞通过TNF的细胞毒性作用介导肿瘤中MDSC的减少。我们的数据为IR、T细胞和PD-L1/PD-1轴之间的密切相互作用提供了证据，并为合理设计免疫调节剂和放疗的联合治疗奠定了基础。
High-dose ionizing irradiation (IR) results in direct tumor cell death and augments tumor-specific immunity, which enhances tumor control both locally and distantly. Unfortunately, local relapses often occur following IR treatment, indicating that IR-induced responses are inadequate to maintain antitumor immunity. Therapeutic blockade of the T cell negative regulator programmed death-ligand 1 (PD-L1, also called B7-H1) can enhance T cell effector function when PD-L1 is expressed in chronically inflamed tissues and tumors. Here, we demonstrate that PD-Li was upregulated in the tumor microenvironment after IR. Administration of anti-PD-L1 enhanced the efficacy of IR through a cytotoxic T cell-dependent mechanism. Concomitant with IR-mediated tumor regression, we observed that IR and anti-PD-L1 synergistically reduced the local accumulation of tumor-infiltrating myeloid-derived suppressor cells (MDSCs), which suppress T cells and alter the tumor immune microenvironment. Furthermore, activation of cytotoxic T cells with combination therapy mediated the reduction of MDSCs in tumors through the cytotoxic actions of TNF. Our data provide evidence for a close interaction between IR, T cells, and the PD-L1/PD-1 axis and establish a basis for the rational design of combination therapy with immune modulators and radiotherapy.