CDH3-directed immunotherapy targets basal-like hormone receptor negative prostate cancer and breast cancer

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Abstract

Basal-like double-negative prostate cancer (DNPC) and triple-negative breast cancer (TNBC) are aggressive tumors with few targeted treatment options, raising the question of whether a shared, druggable cell-surface antigen can be leveraged for effective immunotherapy. Here, we integrated analyses of independent bulk and single-cell transcriptomic datasets with mechanistic and preclinical therapeutic studies to evaluate CDH3 (P-cadherin) as a candidate target in basal-like disease. CDH3 expression was consistently enriched in basal-like subtypes across prostate and breast cancer cohorts and was preferentially expressed in basal epithelial tumor compartments. Mechanistically, CDH3 expression was governed by a YAP1–WNT5A/ROR2 signaling axis, linking basal subtype gene expression to non-canonical Wnt signaling. To exploit this target, we evaluated both a CDH3-directed antibody-drug conjugate (ADC) and CDH3-specific chimeric antigen receptor (CAR)-T cells. The ADC exhibited antigen-dependent internalization and cytotoxicity in vitro and reduced metastatic tumor burden in vivo. CDH3 CAR-T cells showed antigen-specific activation and tumor cell killing in vitro and improved tumor control and survival in metastatic prostate and breast cancer xenograft models, with additional benefit when combined with PD-1 blockade (nivolumab). Together, these findings establish CDH3 as a clinically relevant and therapeutically actionable target and support CDH3-directed ADC and CAR-T strategies for aggressive, basal-like DNPC and TNBC.

Authors

Guoqiang Liu, Shiyu Wang, Ziyu Zeng, Loan Duong, Jing Yang, Nipuni Barupala, Yun Zhao, Sharif Rahmy, Shan Feng, Xiaotian Chi, Ariana Arce, Linchuan Jia, Jun Wan, Liang Cheng, Xuemin Lu, Xin Lu