The expression of antigens that are recognized by self-reactive T cells is essential for immune-mediated tumor rejection by immune checkpoint blockade (ICB) therapy. Growing evidence suggests that mutation-associated neoantigens drive ICB responses in tumors with high mutational burden. In most patients, only a few of the mutations in the cancer exome that are predicted to be immunogenic are recognized by T cells. One factor that limits this recognition is the level of expression of the mutated gene product in cancer cells. Substantial preclinical data show that radiation can convert the irradiated tumor into a site for priming of tumor-specific T cells, that is, an in situ vaccine, and can induce responses in otherwise ICB-resistant tumors. Critical for radiation-elicited T-cell activation is the induction of viral mimicry, which is mediated by the accumulation of cytosolic DNA in the irradiated cells, with consequent activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon (IFN) genes (STING) pathway and downstream production of type I IFN and other pro-inflammatory cytokines. Recent data suggest that radiation can also enhance cancer cell antigenicity by upregulating the expression of a large number of genes that are involved in the response to DNA damage and cellular stress, thus potentially exposing immunogenic mutations to the immune system. Here, we discuss how the principles of antigen presentation favor the presentation of peptides that are derived from newly synthesized proteins in irradiated cells. These concepts support a model that incorporates the presence of immunogenic mutations in genes that are upregulated by radiation to predict which patients might benefit from treatment with combinations of radiotherapy and ICB.

中文翻译：

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放射治疗和抗肿瘤免疫：将免疫原性突变暴露于免疫系统。

自我反应性T细胞识别的抗原的表达对于通过免疫检查点封锁（ICB）治疗进行的免疫介导的肿瘤排斥反应至关重要。越来越多的证据表明，与突变相关的新抗原可驱动具有高突变负担的肿瘤中的ICB反应。在大多数患者中，癌症外显子组中只有少数被预测具有免疫原性的突变被T细胞识别。限制这种识别的一个因素是癌细胞中突变基因产物的表达水平。大量的临床前数据表明，辐射可以将被​​辐射的肿瘤转化为引发肿瘤特异性T细胞（即原位疫苗）的部位，并且可以诱导原本对ICB耐药的肿瘤的反应。辐射诱发的T细胞活化的关键是病毒拟态的诱导，它是由辐射细胞中胞质DNA的积累介导的，随后激活了环GMP-AMP合酶（cGAS）/干扰素（IFN）基因（STING）途径的刺激物，以及下游产生的I型IFN和其他pro-炎性细胞因子。最近的数据表明，辐射还可以通过上调与DNA损伤和细胞应激反应有关的大量基因的表达来增强癌细胞的抗原性，从而可能使免疫原性突变暴露于免疫系统。在这里，我们讨论了抗原呈递的原理如何促进受辐照细胞中新合成蛋白质衍生的肽的呈递。