肿瘤细胞治疗研究
英文原题：Features of tumor microenvironment in HER2-positive urothelial carcinoma and its implications for immunotherapy resistance.
Features of tumor microenvironment in HER2-positive urothelial carcinoma and its implications for immunotherapy resistance.
在机构IHC定义的队列中，HER2阳性UC与TCGA队列中ERBB2扩增的UC均与适应性免疫浸润减少及免疫相关信号传导减弱相关。这些发现支持HER2定义的UC中存在免疫冷表型，并为进一步研究整合HER2靶向治疗与免疫检查点阻断的生物标志物指导联合策略提供了产生假设的证据。
HER2过表达或ERBB2扩增是尿路上皮癌（UC）的重要分子特征，并与免疫检查点抑制剂（ICIs）的差异反应相关。然而，与HER2定义的UC相关的肿瘤微环境（TME）特征及其与ICI反应性的潜在关系仍未完全阐明。
来自本中心52例接受ICIs单药治疗的UC患者的肿瘤组织进行了多重免疫荧光（IF）染色，以评估免疫细胞浸润和免疫检查点蛋白表达。同时，分析了来自The Cancer Genome Atlas（TCGA）中408例UC病例的转录组和体细胞突变数据。基于HER2拷贝数状态（GISTIC评分≥2为扩增）进行了差异基因表达和通路富集分析。使用xCell算法估计bulk RNA-seq数据中的免疫细胞浸润。
在机构队列中，HER2阳性肿瘤的客观缓解率（ORR）和疾病控制率（DCR）在数值上低于HER2阴性肿瘤，尽管这些差异无统计学显著性。多重IF分析显示，HER2阳性肿瘤中CD4⁺ T细胞、CD8⁺ T细胞和CD20⁺ B细胞的浸润减少。HER2阳性肿瘤中PD-1和STING表达也较低，而LAG-3、TIM-3、CTLA-4和PD-L1呈非显著性下降趋势。在TCGA-BLCA队列中，ERBB2扩增肿瘤显示免疫相关通路下调，以及多种免疫细胞群体（包括T细胞、树突状细胞、B细胞、NK细胞和巨噬细胞）的推断浸润减少。
BACKGROUND: HER2 overexpression or ERBB2 amplification represents an important molecular feature of urothelial carcinoma (UC) and has been associated with differential responses to immune checkpoint inhibitors (ICIs). However, the tumor microenvironmental (TME) features associated with HER2-defined UC and their potential relationship with ICI responsiveness remain incompletely characterized. METHODS: Tumor tissues from 52 UC patients treated with ICIs monotherapy at our center underwent multiplex immunofluorescence (IF) staining to evaluate immune cell infiltration and immune checkpoint protein expression. In parallel, transcriptomic and somatic mutation data from 408 UC cases in The Cancer Genome Atlas (TCGA) were analyzed. Differential gene expression and pathway enrichment analyses were performed based on HER2 copy number status (GISTIC score ≥ 2 for amplification). The xCell algorithm was used to estimate immune cell infiltration in bulk RNA-seq data. RESULTS: In the institutional cohort, HER2-positive tumors showed numerically lower objective response rate (ORR) and disease control rate (DCR) than HER2-negative tumors, although these differences were not statistically significant. Multiplex IF analysis revealed reduced infiltration of CD4⁺ T cells, CD8⁺ T cells, and CD20⁺ B cells in HER2-positive tumors. PD-1 and STING expression were also lower in HER2-positive tumors, whereas LAG-3, TIM-3, CTLA-4, and PD-L1 showed non-significant downward trends. In the TCGA-BLCA cohort, ERBB2-amplified tumors showed downregulation of immune-related pathways and reduced inferred infiltration of multiple immune cell populations, including T cells, dendritic cells, B cells, NK cells, and macrophages. CONCLUSIONS: HER2-positive UC in the institutional IHC-defined cohort and ERBB2-amplified UC in the TCGA cohort were associated with reduced adaptive immune infiltration and attenuated immune-related signaling. These findings support the presence of an immune-cold phenotype in HER2-defined UC and provide hypothesis-generating evidence for further investigation of biomarker-guided combination strategies integrating HER2-targeted therapy with immune checkpoint blockade.
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