Khandakar Hena, Kaushal Seema, Seth Amlesh, Sahoo Ranjit K, Narwal Anubhav, Jangir Hemlata, Nayak Brusabhanu, Dinda Amit K
Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
Department of Urology, All India Institute of Medical Sciences, New Delhi, India.
Am J Clin Pathol. 2025 May 17;163(5):708-722. doi: 10.1093/ajcp/aqae176.
Immune checkpoint inhibitors have revolutionized treatment of platinum-refractory advanced bladder cancer, offering hope where options are limited. Response varies, however, influenced by factors such as the tumor's immune microenvironment and prior therapy. Muscle-invasive bladder cancer (MIBC) is stratified into molecular subtypes, with distinct clinicopathologic features affecting prognosis and treatment. This study assessed the expression of programmed cell death 1 ligand 1 (PD-L1) and other immune markers in MIBC, categorized by molecular phenotype.
Using GATA3 and CK5/6 immunohistochemistry, 90 neoadjuvant chemotherapy-naive MIBC cases were classified into luminal and non-luminal subtypes. The immune microenvironment was characterized through immunostaining for PD-L1, CD4, and CD8. We applied PD-L1 positivity thresholds of 1% or greater for tumor cells and 5% or greater for immune cells. Tumors were examined for PD-L1 expression, histologic subtypes, and immune cell infiltration.
Varied expression of PD-L1 and T-cell subtype densities were observed among MIBC subtypes. The double-negative subtype displayed the highest PD-L1 immune cell expression and stromal CD4 and CD8 T-cell densities, indicating an active immune profile. The basal subtype exhibited the highest PD-L1 positivity in tumor cells. In contrast, the luminal type showed the lowest PD-L1 tumor and immune cell expression, with high intratumoral CD4 T-cell density. Although PD-L1 expression in tumor or immune cells did not independently affect survival, patients with basal and double-negative tumors had poorer overall survival.
This study highlighted the immune diversity of MIBC in the context of molecular subtypes. Distinct molecular and immune profiles could guide the development of predictive signatures for enhanced immunotherapy response in advanced bladder cancer.
免疫检查点抑制剂彻底改变了铂类难治性晚期膀胱癌的治疗方式，在选择有限的情况下带来了希望。然而，反应各不相同，受肿瘤免疫微环境和既往治疗等因素影响。肌层浸润性膀胱癌（MIBC）被分为分子亚型，具有影响预后和治疗的独特临床病理特征。本研究评估了程序性细胞死亡1配体1（PD-L1）和其他免疫标志物在按分子表型分类的MIBC中的表达。
使用GATA3和CK5/6免疫组织化学方法，将90例未接受新辅助化疗的MIBC病例分为腔面型和非腔面型亚型。通过对PD-L1、CD4和CD8进行免疫染色来表征免疫微环境。我们将肿瘤细胞的PD-L1阳性阈值设定为1%或更高，免疫细胞的阈值设定为5%或更高。检查肿瘤的PD-L1表达、组织学亚型和免疫细胞浸润情况。
在MIBC亚型中观察到PD-L1的不同表达和T细胞亚型密度。双阴性亚型显示出最高的PD-L1免疫细胞表达以及基质CD4和CD8 T细胞密度，表明免疫活性较高。基底亚型在肿瘤细胞中显示出最高的PD-L1阳性率。相比之下，腔面型显示出最低的PD-L1肿瘤和免疫细胞表达，肿瘤内CD4 T细胞密度较高。虽然肿瘤或免疫细胞中的PD-L1表达并未独立影响生存率，但基底型和双阴性肿瘤患者的总生存率较差。
本研究突出了MIBC在分子亚型背景下的免疫多样性。不同的分子和免疫特征可为晚期膀胱癌增强免疫治疗反应的预测标志物的开发提供指导。
