放疗免疫调节效应研究的进展——从基础到临床  

Advancements in the research of immunomodulatory effects of radiation therapy:from basic to clinical

作　　者：王妤 毕楠 WANG Yu;BI Nan(Department of Radiation Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Science and Peking Union Medical College,Beijing 100021,China)

机构地区：[1]国家癌症中心,国家肿瘤临床医学研究中心,中国医学科学院/北京协和医学院肿瘤医院放疗科,北京100021

出　　处：《中国癌症杂志》2023年第12期1083-1091,共9页China Oncology

摘　　要：既往观点认为,放射治疗主要通过破坏肿瘤细胞脱氧核糖核酸双链直接发挥杀伤肿瘤细胞的作用,近年来研究发现,放疗也可通过上调局部与全身免疫反应,间接产生积极有效的抗肿瘤免疫应答。然而,放疗的免疫调节效应具有双面性,一方面可激活并产生抗肿瘤免疫促进效应,另一方面也可能产生免疫抑制作用。其中,放疗正向调节适应性与固有性抗肿瘤免疫反应的关键分子机制主要包括:诱导免疫原性细胞凋亡从而促进T淋巴细胞的增殖与活化;激活环磷酸鸟苷-腺苷合成酶-干扰素基因刺激蛋白通路引发Ⅰ型干扰素反应;改变肿瘤细胞表型,加强其免疫原性与抗原可视度;刺激肿瘤细胞与基质细胞释放多种炎症因子,重塑肿瘤免疫微环境;上调肿瘤细胞表面免疫检查点以及死亡受体等的表达,促进免疫识别与抗肿瘤免疫应答。而放疗负向抑制免疫反应的主要机制包括:诱导肿瘤细胞上调多种免疫抑制因子的基因表达;增强包括调节性T细胞、髓系来源抑制性细胞在内的多种免疫抑制细胞的功能与作用;导致淋巴细胞的数量减少以及免疫效应细胞的耗竭等。基于以上关于放疗免疫调节效应的机制原理探索,目前在放疗联合免疫治疗的临床实践中也显示出重大的研究进展,包括免疫治疗时代背景下的放疗远隔效应,即放疗照射野以外产生的有效抗肿瘤免疫应答,以及立体定向放疗或低剂量放疗联合免疫检查点抑制剂治疗时显著增加的疗效获益。然而,目前对于放疗联合免疫治疗产生的协同作用机制及其具体影响因素等仍不明确,未来需要在放疗与免疫治疗联合治疗的最佳放疗剂量、放疗分割模式、放疗照射部位与靶区设计、免疫药物选择以及放疗与免疫联合治疗顺序等研究方向开展深入探索,以进一步提高临床疗效,促进放疗免疫调节生物学效应的临床转化应用。本�Previously,radiotherapy was considered to directly kill tumor cells by deoxyribonucleic acid double-strand break.Recent studies have found that radiotherapy can also produce positive and effective anti-tumor effect by upregulating local and systemic immune responses.However,the immunomodulatory effect of radiotherapy is double-sided.On the one hand,it can activate anti-tumor immune-promoting effect,on the other hand,it may also produce immunosuppressive effect.The key molecular mechanisms of the positive regulation of adaptive and innate anti-tumor response by radiotherapy primarily include:induction of immunogenic cell death to promote the proliferation and activation of T lymphocytes;activation of the cyclic GMP-AMP synthasestimulator of interferon genes pathway to induce typeⅠinterferon response;changing the phenotype of tumor cells to enhance their immunogenicity and antigen visibility;stimulating tumor cells and stromal cells to release a variety of inflammatory factors and reshape the tumor immune microenvironment;upregulating the expression of immune checkpoint and death receptor on the surface of tumor cells to promote immune recognition and anti-tumor immune response.In addition,the mechanisms of negative immune suppression by radiotherapy mainly include:induction of tumor cells to upregulate the gene expression of multiple immunosuppressive factors;enhancing the function and effect of various immunosuppressive cells,including regulatory T cells and myeloid-derived suppressor cells;leading to the decreased number of lymphocytes and the depletion of immunologic effector cells.Based on the above exploration of the mechanisms and principle of the immunomodulatory effect of radiotherapy,significant progress has also been shown in the clinical practice of combining radiotherapy with immunotherapy,such as the abscopal effect in the context of immunotherapy era,that is,the effective anti-tumor immune responses generated outside the irradiation field of radiotherapy,as well as the increased efficacy benefit wh

关 键 词：放射治疗 免疫调节 免疫检查点抑制剂 远隔效应 

分 类 号：R730.5[医药卫生—肿瘤]