Dual molecular axis of resistance and immunoresponsiveness to BCG in pT1 non-muscle invasive bladder cancer: Insights from HER-2, SERBP1, HABP4, and IFN-γ profiling

IF 2.5 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-09-15 DOI:10.1016/j.tice.2025.103137

João Carlos Cardoso Alonso , Juliana Mattoso Gonçalves , Gabriela Cardoso de Arruda Camargo , Gabriela de Oliveira , André da Silva Santos , Adriano Angelo Cintra , Fabio Guimaraes , Leandro Luiz Lopes de Freitas , Martim Corrêa Bottene , Jean Felipe Prodocimo Lestingi , Jörg Kobarg , Wagner José Fávaro

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引用次数: 0

Abstract

Bacillus Calmette–Guérin (BCG) immunotherapy remains the cornerstone of adjuvant treatment for high-risk non–muscle invasive bladder cancer (NMIBC); however, therapeutic failure is particularly frequent in pT1 disease, resulting in early recurrence and progression to muscle-invasive cancer. Identifying biomarkers to anticipate BCG failure is a current clinical priority to improve patient stratification and enable risk-adapted, bladder-sparing interventions. We retrospectively analyzed a cohort of 48 patients with histologically confirmed pT1 NMIBC treated with standard intravesical BCG at two tertiary centers. The median age was 67 years (range: 41–93), 79.2 % were male, 81.2 % had high-grade tumors, 70.8 % had multifocal lesions, and 75.0 % presented tumors > 3 cm. Formalin-fixed, paraffin-embedded tumor samples were obtained prior to BCG and, when available, at recurrence or progression. Immunohistochemical expression of HER-2, SERBP1, HABP4, and IFN-γ was quantified using semi-quantitative scoring and H-scores. Associations with recurrence-free survival (RFS) and progression-free survival (PFS) were evaluated using Kaplan–Meier survival analysis and Cox regression. HER-2 and SERBP1 were significantly overexpressed in BCG-refractory tumors, with high immunorectivities conferring markedly reduced RFS (HER-2: 7.78 vs. 11.71 months, p < 0.001; SERBP1: 7.64 vs. 11.52 months, p < 0.0001) and inferior PFS (p < 0.05). In contrast, high HABP4 and IFN-γ immunorectivities were strongly associated with sustained recurrence- and progression-free survival (both p < 0.0001). Hazard ratios for recurrence and progression exceeded 5.0 for HER-2/SERBP1-high and IFN-γ/HABP4-low profiles. These findings define two molecular phenotypes—immune-evasive versus immune-active—that may inform precision risk stratification, early intervention, and personalized therapeutic decision-making in high-risk NMIBC.

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pT1非肌肉浸润性膀胱癌中卡介苗耐药和免疫应答的双分子轴：来自HER-2、SERBP1、HABP4和IFN-γ谱分析的见解

卡介苗免疫疗法仍然是高危非肌肉浸润性膀胱癌（NMIBC）辅助治疗的基石；然而，治疗失败在pT1疾病中尤其常见，导致早期复发和进展为肌肉侵袭性癌症。识别生物标志物以预测卡介苗失败是当前的临床优先事项，以改善患者分层，实现适应风险的膀胱保护干预。我们回顾性分析了48例组织学证实的pT1型NMIBC患者，他们在两个三级中心接受了标准膀胱内卡介苗治疗。中位年龄为67岁（范围：41-93岁），79.2% %为男性，81.2% %为高级别肿瘤，70.8% %为多灶性病变，75.0% %为肿瘤> 3 cm。在卡介苗治疗之前获得福尔马林固定石蜡包埋的肿瘤样本，如果有的话，在复发或进展时获得。采用半定量评分法和h评分法定量HER-2、SERBP1、HABP4和IFN-γ的免疫组化表达。使用Kaplan-Meier生存分析和Cox回归评估与无复发生存（RFS）和无进展生存（PFS）的关联。HER-2和SERBP1在bcg难治性肿瘤中显著过表达，高免疫活性使RFS显著降低(HER-2: 7.78 vs. 11.71月，p

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来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.