A TROP2/Claudin program mediates immune exclusion to impede checkpoint blockade in breast cancer 2059

Description Immune exclusion inhibits anti-tumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. Here, we demonstrate that Trophoblast Cell-Surface Antigen 2 (TROP2), a key target of emerging anti-cancer Antibody Drug Conjugates (ADCs), controls barrier-mediated immune exclusion in Triple-Negative Breast Cancer (TNBC) through Claudin 7 association and tight junction regulation. 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 tight junction proteins, 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. Thus, TROP2 controls an immune exclusion program that can be targeted to enhance immunotherapy response. Funding Sources This work was supported by DOD/CDMRP Grant BC200924 and by R01CA260890 (to L.W. Ellisen, A. Bardia), by the Tracey Davis Memorial Breast Cancer Research Fund (to L.W. Ellisen), and by NIH/NCI K99CA286969 and The Terri Brodeur Breast Cancer Foundation Fellowship (to B. Wu). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)