Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Cancer Immunol Res. 2015 Apr;3(4):345-55. doi: 10.1158/2326-6066.CIR-14-0196. Epub 2014 Dec 19.
The immune-modulating effects of radiotherapy (XRT) have gained considerable interest recently, and there have been multiple reports of synergy between XRT and immunotherapy. However, additional preclinical 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 XRT to induce endogenous antigen-specific immune responses when it is combined with anti-PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image-guided stereotactic XRT delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T cell- and B cell-mediated immune responses. These immune-stimulating effects of XRT were significantly increased when XRT was 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 XRT increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically, we found that XRT upregulates tumor-associated antigen-MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increases T-cell infiltration into tumors. These findings demonstrate the ability of XRT to prime an endogenous antigen-specific immune response and provide an additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic.
放疗（XRT）的免疫调节作用最近引起了相当大的兴趣，并且有多项报告表明 XRT 与免疫疗法之间存在协同作用。然而，需要更多的临床前研究来证明放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 XRT 与抗 PD-1 检查点阻断免疫疗法联合使用时，能够诱导内源性抗原特异性免疫反应。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的立体定向 XRT 治疗，导致了抗原特异性 T 细胞和 B 细胞介导的免疫反应的发展。当 XRT 与抗 PD-1 治疗或调节性 T 细胞（Treg）耗竭联合使用时，XRT 的这些免疫刺激作用显著增加，导致局部肿瘤控制得到改善。对抗原特异性 CD8 T 细胞的表型分析表明，XRT 增加了抗原经验丰富的 T 细胞和效应记忆 T 细胞的百分比。从机制上讲，我们发现 XRT 上调了肿瘤相关抗原-MHC 复合物，增强了引流淋巴结中的抗原交叉呈递，并增加了 T 细胞浸润到肿瘤中。这些发现证明了 XRT 诱导内源性抗原特异性免疫反应的能力，并为临床中放射与 PD-1 阻断联合提供了额外的机制依据。
