Gong Caifeng, Zhang Wen, Sun Yongkun, Shou Jianzhong, Jiang Zhichao, Liu Tianyi, Wang Shengzhou, Liu Jun, Sun Ying, Zhou Aiping
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
iScience. 2023 Apr 23;26(6):106720. doi: 10.1016/j.isci.2023.106720. eCollection 2023 Jun 16.
The immune-genetic changes that occur in cancer patients experiencing hyperprogressive disease (HPD) during combined immunotherapy are unclear. In this study, HPD patients with pre- and post-HPD samples and non-HPD patients with solid tumors were molecularly characterized by genetic and tumor immune microenvironment (TiME) analyses of paired samples by whole-exome sequencing, RNA sequencing, and multiplex immunofluorescence. The genetic analysis of paired samples showed that almost all the tumor driver gene mutations were preserved between pre- and post-HPD tumors HPD patients had higher frequencies of mutations in and , and a significantly higher mutant-allele tumor heterogeneity than non-HPD patients. Tumor IL-6 mRNA was upregulated in post-HPD samples vs. pre-HPD, accompanied by a potential immune suppressive TiME with an elevated M2/M1 ratio. Salvage treatment with irinotecan plus bevacizumab was effective in one HPD patient, who experienced prolonged survival. These genetic features and TiME characteristics might help identify the features of HPD after immunotherapy.
癌症患者在联合免疫治疗期间出现超进展性疾病（HPD）时发生的免疫遗传变化尚不清楚。在本研究中，对有HPD前后样本的HPD患者以及患有实体瘤的非HPD患者，通过全外显子测序、RNA测序和多重免疫荧光对配对样本进行基因和肿瘤免疫微环境（TiME）分析，从而进行分子特征分析。配对样本的基因分析表明，几乎所有肿瘤驱动基因突变在HPD前后的肿瘤之间都得以保留，HPD患者在 和 中的突变频率更高，且突变等位基因肿瘤异质性显著高于非HPD患者。与HPD前样本相比，HPD后样本中的肿瘤IL-6 mRNA上调，同时伴随着潜在的免疫抑制性TiME，M2/M1比值升高。一名HPD患者接受伊立替康联合贝伐单抗的挽救治疗有效，生存期延长。这些基因特征和TiME特征可能有助于识别免疫治疗后HPD的特征。
