Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen.
Stereotactic Radiation Therapy Augments Antigen-Specific PD-1-Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen.
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DOI：
10.1158/2326-6066.cir-14-0196
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发表时间：
2015-04
影响因子：
10.1
通讯作者：
Drake CG
中科院分区：
文献类型：
--
作者：
Sharabi AB;Nirschl CJ;Kochel CM;Nirschl TR;Francica BJ;Velarde E;Deweese TL;Drake CG
放射治疗的免疫调节作用最近引起了人们极大的兴趣，并且有多个关于放射治疗和免疫治疗之间协同作用的报道。然而，还需要更多的临床前研究来证明辐射诱导的免疫反应的抗原特异性，并阐明与免疫疗法协同作用的潜在机制。在这里，我们证明了立体定向放射治疗与抗 PD-1 检查点阻断免疫治疗相结合时诱导内源性抗原特异性免疫反应的能力。使用小动物放射研究平台 (SARRP)，对 B16-OVA 黑色素瘤或 4T1-HA 乳腺癌肿瘤进行图像引导立体定向放射治疗，导致抗原特异性 T 和 B 细胞介导的免疫反应的发展。当与抗 PD-1 疗法或调节性 T 细胞 (Treg) 耗竭相结合时，放射疗法的这些免疫刺激作用显着增强，从而改善局部肿瘤控制。抗原特异性 CD8 T 细胞的表型分析表明，放疗增加了抗原经历过的 T 细胞和效应记忆 T 细胞的百分比。从机制上讲，我们发现放疗上调肿瘤相关抗原-MHC 复合物，增强引流淋巴结中的抗原交叉呈递，并增加 T 细胞浸润到肿瘤中。这些发现证明了放疗能够引发内源性抗原特异性免疫反应，并为临床上将放疗与 PD-1 阻断相结合提供了额外的机制原理。
The immune-modulating effects of radiation therapy have gained considerable interest recently and there have been multiple reports of synergy between radiation and immunotherapy. However, additional pre-clinical studies are needed to demonstrate the antigen-specific nature of radiation-induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here we demonstrate the ability of stereotactic radiotherapy to induce endogenous antigen-specific immune responses when combined with anti-PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image-guided stereotactic radiotherapy delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T and B cell-mediated immune responses. These immune-stimulating effects of radiotherapy were significantly increased when combined with either anti-PD-1 therapy or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that radiotherapy increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically we found that radiotherapy up-regulates tumor-associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increased T-cell infiltration into tumors. These findings demonstrate the ability of radiotherapy to prime an endogenous antigen-specific immune response and provide additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic.