文章 : 

帕博利珠单抗联合放疗在免疫学冷表型非小细胞肺癌中诱导系统性抗肿瘤免疫应答

Combination of pembrolizumab and radiotherapy induces systemic antitumor immune responses in immunologically cold non-small cell lung cancer

原文发布日期：2025-07-22

英文摘要：

The abscopal effects of radiation may sensitize immunologically cold tumors to immune checkpoint inhibition. We investigated the immunostimulatory effects of radiotherapy leveraging multiomic analyses of serial tissue and blood biospecimens (n = 293) from a phase 2 clinical trial of stereotactic body radiation therapy (SBRT) followed by pembrolizumab in metastatic non-small cell lung cancer (NCT02492568). Participants with immunologically cold tumors (low tumor mutation burden, null programmed death ligand 1 expression or Wnt pathway mutations) had significantly longer progression-free survival in the SBRT arm. Induction of interferon-γ, interferon-α and antigen processing and presentation gene sets was significantly enriched after SBRT in nonirradiated tumor sites. Significant on-therapy expansions of new and pre-existing T cell clones in both the tumor (abscopal) and the blood (systemic) compartments were noted alongside clonal neoantigen-reactive autologous T cell responses in participants with long-term survival after radioimmunotherapy. These findings support the systemic immunomodulatory and antitumor effects of radioimmunotherapy and may open a therapeutic window of opportunity to overcome immunotherapy resistance.

摘要翻译：

放射治疗的远隔效应或可增强免疫学"冷肿瘤"对免疫检查点抑制的敏感性。我们通过多组学分析手段，对一项评估立体定向放射治疗（SBRT）联合帕博利珠单抗治疗转移性非小细胞肺癌的II期临床试验（NCT02492568）中连续采集的组织与血液生物样本（n=293）进行了研究。结果显示，在具有免疫学冷肿瘤特征（低肿瘤突变负荷、程序性死亡配体1表达缺失或Wnt通路突变）的受试者中，SBRT治疗组无进展生存期显著延长。放射治疗后，未照射肿瘤部位显著富集了干扰素-γ、干扰素-α以及抗原加工呈递相关基因集的诱导表达。值得注意的是，在肿瘤（远隔效应）和血液（全身系统）中均观察到治疗期间新发及既存T细胞克隆的显著扩增，同时在接受放射免疫联合治疗获得长期生存的受试者中检测到克隆性新抗原反应性自体T细胞应答。这些发现证实了放射免疫治疗的系统性免疫调节与抗肿瘤效应，或可为克服免疫治疗耐药性开启新的治疗时间窗。

原文链接：

https://www.nature.com/articles/s43018-025-01018-w