Abstract PR-04: A TROP2/Claudin program mediates immune exclusion to impede checkpoint blockade in breast cancer

Abstract Background: Antibody Drug Conjugates (ADCs) targeting Trophoblast Cell-Surface Antigen 2 (TROP2) are emerging as paradigm-changing drugs, but the therapeutically relevant mechanisms of TROP2 itself remain unknown. The goal of this project is to investigate the role of TROP2 in promoting breast cancer aggressiveness and provide insights into the mechanisms of action of TROP2-targeted ADCs. Methods: TROP2 loss-of-function studies were performed in multiple syngeneic mouse mammary tumor models. Truncated TROP2 mutants were reconstituted into CRISPR knockout cells to map essential domains that enable TROP2 tumor-promoting activity. Flow cytometry for tumor infiltrating lymphocytes, tissue histology and immunofluorescence were used to assess tumor microenvironment. Data from immune checkpoint-treated patients were used to test hypotheses from the preclinical findings. Results: We find that TROP2 mediates a mechanism of immune exclusion in Triple-Negative Breast Cancer (TNBC) through association with the essential tight junction protein Claudin 7. TROP2 expression is inversely correlated with T cell infiltration and strongly associated with 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 claudins, enabling T cell infiltration. Employing a humanized TROP2 syngeneic TNBC model, we show that TROP2 targeting via Sacituzumab govitecan (SG) induces an anti-PD1 response associated with broad immune cell activation, and TROP2 is highly associated with lack of response to anti-PD1 therapy in human breast cancer. Conclusions: TROP2 mediates immune exclusion and may be targeted to enhance immunotherapy response. Citation Format: Bogang Wu, Win Thant, Elena Bitman, Ting Liu, Jie Liu, Eleftherios I. Paschalis, Katherine H. Xu, Linda T. Nieman, David T. Ting, Nayana Thimmiah, Sheng Sun, Rachel O. Abelman, Steven J. Isakoff, Laura M. Spring, Aditya Bardia, Leif W. Ellisen. A TROP2/Claudin program mediates immune exclusion to impede checkpoint blockade in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr PR-04.