a Department of Pathology, New York University School of Medicine, and NYU Cancer Institute, New York, New York 10016.
Radiat Res. 2014 Aug;182(2):170-81. doi: 10.1667/RR13500.1. Epub 2014 Jun 17.
The main role of the immune system is to restore tissue homeostasis when altered by pathogenic processes, including neoplastic transformation. Immune-mediated tumor rejection has been recognized as an extrinsic tumor suppressor mechanism that tumors need to overcome to progress. By the time a tumor becomes clinically apparent it has successfully escaped immune control by establishing an immunosuppressive microenvironment. Ionizing radiation applied locally to a tumor alters these tumor-host interactions. Accumulating evidence indicates that standard therapeutic doses of radiation have the potential to recover tumor immunogenicity and convert the tumor into an in situ personalized vaccine. Radiotherapy induces an immunogenic tumor cell death promoting cross-presentation of tumor-derived antigens by dendritic cells to T cells. In addition, radiotherapy stimulates chemokine-mediated recruitment of effector T cells to the tumor, and cellular recognition and killing by T cells that is facilitated by upregulation of major histocompatibility antigens, NKG2D ligands, adhesion molecules and death receptors. Despite these effects, radiotherapy alone is only rarely capable of generating enough proinflammatory signals to sufficiently overcome suppression, as it can also activate immunosuppressive factors. However, our group and others have shown that when combined with targeted immunotherapy agents radiotherapy significantly contributes to a therapeutically effective anti-tumor immune response. To illustrate this partnership between radiation and immunotherapy we will discuss as an example our experience in preclinical models and the molecular mechanisms identified. Additionally, the clinical translation of these combinations will be discussed.
免疫系统的主要作用是在受到致病过程（包括肿瘤转化）影响时恢复组织的内稳态。免疫介导的肿瘤排斥已被认为是肿瘤进展时需要克服的外在肿瘤抑制机制。当肿瘤在临床上变得明显时，它已经通过建立一个免疫抑制的微环境成功地逃脱了免疫控制。局部应用于肿瘤的电离辐射改变了这些肿瘤-宿主的相互作用。越来越多的证据表明，标准治疗剂量的辐射有可能恢复肿瘤的免疫原性，并将肿瘤转化为原位个体化疫苗。放射治疗诱导免疫原性肿瘤细胞死亡，促进树突状细胞对 T 细胞交叉呈递肿瘤源性抗原。此外，放射治疗还刺激趋化因子介导的效应 T 细胞向肿瘤募集，以及 T 细胞的细胞识别和杀伤，这得益于主要组织相容性抗原、NKG2D 配体、黏附分子和死亡受体的上调。尽管有这些作用，但放射治疗本身很少能够产生足够的促炎信号来充分克服抑制，因为它也可以激活免疫抑制因子。然而，我们小组和其他小组已经表明，当与靶向免疫治疗药物联合使用时，放射治疗显著有助于产生有效的抗肿瘤免疫反应。为了说明辐射和免疫疗法之间的这种伙伴关系，我们将以我们在临床前模型中的经验和确定的分子机制为例进行讨论。此外，还将讨论这些组合的临床转化。
