Abstract PS3-12-29: Trop2 remodeling of the immune microenvironment in triple negative breast cancer

Abstract Immune exclusion inhibits anti-tumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. To identify mechanisms regulating immune infiltration in TNBC, we performed spatial transcriptomic analysis comparing immune-enriched versus immune-cold tumors. We reveal that Trophoblast Cell-Surface Antigen 2 (TROP2), a key target of anti-cancer Antibody Drug Conjugates (ADCs), controls barrier-mediated immune exclusion in TNBC through Claudin 7 association and tight junction regulation. TROP2 expression is inversely correlated with T cell infiltration and predicts poor outcomes in TNBC. Loss-of-function and reconstitution experiments demonstrate TROP2 is sufficient to drive tumor progression in vivo in a CD8 T cell-dependent manner, while its loss deregulates expression and localization of multiple tight junction proteins, enabling T cell infiltration. Employing a humanized TROP2 syngeneic TNBC model, we show that TROP2 targeting via hRS7, the antibody component of the ADC Sacituzumab govitecan (SG), enhances the anti-PD1 response and improves T cell accessibility and effector function. Correspondingly, TROP2 expression is highly associated with lack of response to anti-PD1 therapy in human breast cancer. Thus, TROP2 controls an immune exclusion program that can be targeted to enhance immunotherapy response. Citation Format: B. Wu, W. Thant, E. Bitman, T. Liu, J. Liu, E. Paschalis, B. Patel, C. Nawrocki, K. Xu, L. Nieman, D. Ting, N. Thimmiah, S. Sun, R. Abelman, V. Bossuyt, S. Isakoff, L. Spring, A. Bardia, L. Ellisen. Trop2 remodeling of the immune microenvironment in triple negative breast cancer abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-12-29.