The Clinical Relevance of Tertiary Lymphoid Structures in Assessing Treatment Response in Muscle-Invasive Bladder Cancer.

Abstract

Radical cystectomy (RC) is a standard of care for muscle-invasive bladder cancer (MIBC). Although radiation therapy (RT) offers bladder preservation with comparable survival, 20%-30% of patients require salvage RC. Neoadjuvant chemotherapy (NAC) is given to patients prior to RC, but with modest benefit and considerable toxicity. Among tumor immune microenvironment features, tertiary lymphoid structures (TLS) have emerged as prognostic and predictive biomarkers. Here, we investigate the association between TLS and response to RT and NAC in MIBC. We evaluated TLS in pre-treatment transurethral resection of bladder tumor specimens from MIBC patients given RT or NAC. Multiplex immunohistochemistry defined TLS presence, density, and maturation, including germinal center and immune subset markers. Associations with treatment response and survival were analyzed separately for RT and NAC cohorts. TLS were detected in 83% of RT patients. Although the presence was not prognostic, higher density and maturation correlated with response and with improved overall and cancer-specific survival. Furthermore, TLS density correlated with B cells and regulatory T cells (Tregs) in responders and inversely with cytotoxic T cells in nonresponders. In the NAC cohort, TLS presence, density, or maturation were not associated with response or survival. These exploratory findings suggest that TLS density and maturation may be associated with improved RT outcomes in MIBC and warrant prospective validation as biomarkers.