PD-1 Blockade Boosts Radiofrequency Ablation-Elicited Adaptive Immune Responses against Tumor.
PD-1 Blockade Boosts Radiofrequency Ablation-Elicited Adaptive Immune Responses against Tumor.
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DOI：
10.1158/1078-0432.ccr-15-1352
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发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Jiang J
中科院分区：
文献类型：
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作者：
Shi L;Chen L;Wu C;Zhu Y;Xu B;Zheng X;Sun M;Wen W;Dai X;Yang M;Lv Q;Lu B;Jiang J
射频消融 (RFA) 已被证明可以引发肿瘤特异性 T 细胞免疫反应，但不足以阻止癌症进展。在这里，我们研究了限制 RFA 功效的免疫抑制机制。我们对同时性结直肠癌肝转移患者进行了一项回顾性病例对照研究，这些患者接受了原发性肿瘤切除术，并接受或不接受术前针对肝转移的 RFA。通过免疫组织化学分析人结直肠癌组织中肿瘤浸润 T 细胞和肿瘤 PD-L1 的表达。 T 细胞免疫反应和 PD-1/PD-L1 表达也在 RFA 小鼠模型中进行了表征。此外，还在小鼠 RFA 模型中评估了 RAF 和 PD-1 阻断的联合效应。我们发现，肝转移瘤的 RFA 治疗不仅增加了原发性人类结直肠肿瘤中的 T 细胞浸润，还增加了 PD-L1 表达。使用小鼠肿瘤模型，我们证明了对一种肿瘤的 RFA 治疗最初增强了肿瘤中强烈的 T 细胞介导的免疫反应。然而，肿瘤通过抑制 CD8+ 和 CD4+T 细胞的功能、驱动 Treg 与 Teff 比率升高以及 PD-L1/PD-1 表达上调，很快克服了免疫反应。此外，我们确定 RFA 和抗 PD-1 抗体的联合治疗可显着增强 T 细胞免疫反应，从而增强抗肿瘤免疫力并延长生存期。 PD-L1/PD-1 轴在抑制 RFA 诱导的抗肿瘤免疫反应中发挥着关键作用。这项研究为在临床环境中结合 RFA 和 PD-L1/PD-1 阻断提供了强有力的理由。
Radiofrequency ablation (RFA) has been shown to elicit tumor-specific T cell immune responses but is not sufficient to prevent cancer progression. Here we investigated immune suppressive mechanisms limiting the efficacy of RFA. We performed a retrospective case-controlled study on patients with synchronous colorectal cancer liver metastases who had received primary tumor resection with or without pre-operative RFA for liver metastases. Tumor infiltrating T cells and tumoral PD-L1 expression in human colorectal cancer tissues were analyzed by immunohistochemistry. T cell immune responses and PD-1/PD-L1 expression were also characterized in a RFA mouse model. In addition, the combined effect of RAF and PD-1 blockade was evaluated in the mouse RFA model. We found that RFA treatment of liver metastases increased not only T cell infiltration but also PD-L1 expression in primary human colorectal tumors. Using mouse tumor models, we demonstrated that RFA treatment of one tumor initially enhanced a strong T cell-mediated immune response in tumor. Nevertheless, tumor quickly overcame the immune responses by inhibiting the function of CD8+ and CD4+T cells, driving a shift to higher Treg to Teff ratio, and up-regulating of PD-L1/PD-1 expression. Furthermore, we established that the combined therapy of RFA and anti-PD-1 antibodies significantly enhanced T cell immune responses, resulting in stronger antitumor immunity and prolonged survival. The PD-L1/PD-1 axis plays a critical role in dampening RFA-induced antitumor immune responses. And this study provides a strong rationale for combining RFA and the PD-L1/PD-1 blockade in the clinical setting.