Department of Radiation Oncology and.
Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York, USA.
J Clin Invest. 2021 Mar 1;131(5). doi: 10.1172/JCI138740.
Neoantigens generated by somatic nonsynonymous mutations are key targets of tumor-specific T cells, but only a small number of mutations predicted to be immunogenic are presented by MHC molecules on cancer cells. Vaccination studies in mice and patients have shown that the majority of neoepitopes that elicit T cell responses fail to induce significant antitumor activity, for incompletely understood reasons. We report that radiotherapy upregulates the expression of genes containing immunogenic mutations in a poorly immunogenic mouse model of triple-negative breast cancer. Vaccination with neoepitopes encoded by these genes elicited CD8+ and CD4+ T cells that, whereas ineffective in preventing tumor growth, improved the therapeutic efficacy of radiotherapy. Mechanistically, neoantigen-specific CD8+ T cells preferentially killed irradiated tumor cells. Neoantigen-specific CD4+ T cells were required for the therapeutic efficacy of vaccination and acted by producing Th1 cytokines, killing irradiated tumor cells, and promoting epitope spread. Such a cytotoxic activity relied on the ability of radiation to upregulate class II MHC molecules as well as the death receptors FAS/CD95 and DR5 on the surface of tumor cells. These results provide proof-of-principle evidence that radiotherapy works in concert with neoantigen vaccination to improve tumor control.
体细胞非同义突变产生的新抗原是肿瘤特异性 T 细胞的关键靶点，但只有少数被预测具有免疫原性的突变由癌细胞上的 MHC 分子呈递。在小鼠和患者中的疫苗接种研究表明，引起 T 细胞反应的大多数新表位由于尚未完全了解的原因未能诱导显著的抗肿瘤活性。我们报告放射治疗上调了三阴性乳腺癌免疫原性低的小鼠模型中含有免疫原性突变的基因的表达。用这些基因编码的新表位进行疫苗接种可引发 CD8+和 CD4+T 细胞，虽然不能预防肿瘤生长，但可提高放射治疗的疗效。从机制上讲，新抗原特异性 CD8+T 细胞优先杀死放射后的肿瘤细胞。新抗原特异性 CD4+T 细胞是疫苗接种疗效所必需的，其通过产生 Th1 细胞因子、杀死放射后的肿瘤细胞以及促进表位扩展来发挥作用。这种细胞毒性活性依赖于辐射上调肿瘤细胞表面的 II 类 MHC 分子以及 Fas/CD95 和 DR5 死亡受体的能力。这些结果提供了初步证据，证明放射治疗与新抗原疫苗接种协同作用以改善肿瘤控制。
