Xiao Jiatong, Liu Jinhui, Zhang Chunyu, Liu Zhi, Nie Zhenyu, Yi Zhenglin, Gao Xin, Liang Haisu, Huang Jinliang, Cai Zhiyong, Yan Luzhe, Wu Bingquan, Liu Zefu, Chen Jinbo, Zu Xiongbing, Hu Jiao
Xiangya Hospital Central South University, Changsha, Hunan, China.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
J Immunother Cancer. 2025 Aug 11;13(8):e011881. doi: 10.1136/jitc-2025-011881.
Immune checkpoint inhibitors have shown limited response rates in bladder cancer. RC48-antibody-drug conjugate (ADC) shows potential for combination with immune checkpoint inhibitors. This study aimed to elucidate RC48-ADC's mechanism in sensitizing tumors to immunotherapy and identify optimal combination strategies.
Bioinformatics (The Cancer Genome Atlas, GEO, Xiangya cohorts) analyzed correlations between HER2, immune markers, and therapy response. The h-HER2-MB49 and sg-PD-L1-MB49 cell line was generated. In vitro/vivo models assessed RC48-ADC's impact on the tumor immune microenvironment using flow cytometry, immunofluorescence, co-culture, chemotaxis, CUT&Tag assays, transcriptomics, and ELISA. Subcutaneous tumor models evaluated combination therapies. At the clinical level, bladder cancer immune therapy cohort tissue microarrays were used, and the aforementioned mechanisms were validated using immunohistochemistry and immunofluorescence.
HER2 expression is associated with an inhibitory tumor immune microenvironment and resistance to immunotherapy. RC48-ADC treatment can reactivate this HER2-related inhibitory tumor immune microenvironment, thereby enhancing immunotherapy effectiveness. Mechanistically, RC48-ADC reactivates the tumor immune microenvironment by reducing PD-L1 transcription via Hippo pathway activation. It also promotes the release of chemokines (CCL5, CXCL9, and CXCL14) and recruits cytotoxic T-lymphocytes. In preclinical mouse models, RC48-ADC synergized with CTLA-4 and PD-L1 antibodies.
RC48-ADC enhances immunotherapy by regulating PD-L1 through the Hippo-TAZ pathway and reactivating CD8+T cells, offering a novel combination therapeutic strategy for bladder cancer.
免疫检查点抑制剂在膀胱癌中的反应率有限。RC48抗体药物偶联物（ADC）显示出与免疫检查点抑制剂联合使用的潜力。本研究旨在阐明RC48-ADC使肿瘤对免疫治疗敏感的机制，并确定最佳联合策略。
生物信息学（癌症基因组图谱、GEO、湘雅队列）分析了HER2、免疫标志物与治疗反应之间的相关性。构建了h-HER2-MB49和sg-PD-L1-MB49细胞系。体外/体内模型使用流式细胞术、免疫荧光、共培养、趋化性、CUT&Tag分析、转录组学和酶联免疫吸附测定评估RC48-ADC对肿瘤免疫微环境的影响。皮下肿瘤模型评估联合治疗。在临床水平上，使用膀胱癌免疫治疗队列组织芯片，并通过免疫组织化学和免疫荧光验证上述机制。
HER2表达与抑制性肿瘤免疫微环境及对免疫治疗的抗性相关。RC48-ADC治疗可重新激活这种与HER2相关的抑制性肿瘤免疫微环境，从而提高免疫治疗效果。机制上，RC48-ADC通过激活Hippo通路减少PD-L1转录来重新激活肿瘤免疫微环境。它还促进趋化因子（CCL5、CXCL9和CXCL14）的释放并募集细胞毒性T淋巴细胞。在临床前小鼠模型中，RC48-ADC与CTLA-4和PD-L1抗体协同作用。
RC48-ADC通过Hippo-TAZ通路调节PD-L1并重新激活CD8+T细胞来增强免疫治疗，为膀胱癌提供了一种新的联合治疗策略。
