The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation.
The optimal partnership of radiation and immunotherapy: from preclinical studies to clinical translation.
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DOI：
10.1667/rr13500.1
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发表时间：
2014-08
影响因子：
3.4
通讯作者：
Formenti SC
中科院分区：
文献类型：
--
作者：
Demaria S;Pilones KA;Vanpouille-Box C;Golden EB;Formenti SC
免疫系统的主要作用是恢复组织稳态，当病理过程改变，包括肿瘤转化。免疫介导的肿瘤排斥反应被认为是肿瘤发展需要克服的一种外源性肿瘤抑制机制。当肿瘤在临床上变得明显时，它已经通过建立免疫抑制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与宿主的相互作用。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性化疫苗。放射治疗诱导免疫原性肿瘤细胞死亡，促进树突状细胞向T细胞交叉呈递肿瘤源性抗原。此外，放疗刺激趋化因子介导的效应T细胞向肿瘤募集，并通过上调主要组织相容性抗原、NKG2D配体、粘附分子和死亡受体促进T细胞对细胞的识别和杀伤。尽管有这些作用，单独放疗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，我们的团队和其他人已经表明，当与靶向免疫治疗剂联合使用放射治疗时，可显著促进治疗有效的抗肿瘤免疫反应。为了说明放射和免疫治疗之间的这种伙伴关系，我们将以临床前模型和确定的分子机制为例讨论我们的经验。此外，这些组合的临床翻译将被讨论。
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.