Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma^1-3, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor^4-6. The latter is essential for achieving abscopal responses in murine cancers⁶. The mechanisms underlying abscopal responses in patients treated with radiation therapy and CTLA-4 blockade remain unclear. Here we report that radiation therapy and CTLA-4 blockade induced systemic anti-tumor T cells in chemo-refractory metastatic non-small-cell lung cancer (NSCLC), where anti-CTLA-4 antibodies had failed to demonstrate significant efficacy alone or in combination with chemotherapy^7,8. Objective responses were observed in 18% of enrolled patients, and 31% had disease control. Increased serum interferon-β after radiation and early dynamic changes of blood T cell clones were the strongest response predictors, confirming preclinical mechanistic data. Functional analysis in one responding patient showed the rapid in vivo expansion of CD8 T cells recognizing a neoantigen encoded in a gene upregulated by radiation, supporting the hypothesis that one explanation for the abscopal response is radiation-induced exposure of immunogenic mutations to the immune system.

中文翻译：

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放疗诱导肺癌对 CTLA-4 阻断的反应。


在临床前研究和一些黑色素瘤患者中，局部放射治疗可增强抗 CTLA-4 抗体的全身反应^1-3 ，但其诱导对 CTLA-4 阻断无反应的肿瘤的全身反应（远隔反应）的功效仍不确定。放射治疗促进抗肿瘤 T 细胞的激活，这种作用依赖于受辐射肿瘤中 I 型干扰素的诱导^4-6 。后者对于实现小鼠癌症的远隔反应至关重要⁶ 。接受放射治疗和 CTLA-4 阻断治疗的患者远隔反应的机制仍不清楚。在这里，我们报告放射治疗和 CTLA-4 阻断在化疗难治性转移性非小细胞肺癌 (NSCLC) 中诱导全身性抗肿瘤 T 细胞，其中抗 CTLA-4 抗体单独或在治疗中未能表现出显着疗效。与化疗联合使用^7,8 。 18% 的入组患者观察到客观缓解，31% 的疾病得到控制。放疗后血清干扰素-β 增加和血液 T 细胞克隆的早期动态变化是最强的反应预测因子，证实了临床前机制数据。对一名有反应的患者进行的功能分析显示，CD8 T 细胞在体内快速扩增，识别辐射上调基因中编码的新抗原，这支持了这样一种假设，即远隔反应的一种解释是辐射诱导免疫系统暴露于免疫原性突变。