Abstract 7241: Tumor-derived APi1 inhibits antigen cross-presentation in dendritic cells and impairs anti-tumor immunity in breast cancer

Abstract Tumor mutational burden (TMB), usually representing high immunogenicity, could not always predict treatment response of immune checkpoint blockade (ICB). Here, we showed that defective antigen cross-presentation in type 1 conventional dendritic cells (cDC1) was responsible for lacking tumor-specific cytotoxic T lymphocytes (CTLs) in triple-negative breast cancer (TNBC) patients. Mechanistically, we found a tumor-derived protein, termed antigen presentation inhibitor 1 (APi1) , was shuttled via extracellular vesicles (EVs) into the endosomes of intratumor DCs, inhibited antigen cross-presentation by locking antigen binding to HSP90 and precluding their translocation from endosomes to cytoplasm. APi1 knockdown in tumor cells or inhibiting APi1/HSP90 interaction in DCs efficiently promoted antigen translocation and enhanced their cross-presentation, which improved ICB therapeutic responses. Clinically, high tumor APi1 expression was associated with low infiltration of antigen-specific CTLs and poor ICB efficacy in TNBC patients. Therefore, tumor EV-shuttled APi1 locks antigen/chaperone interaction and impairs antigen cross-presentation in DCs. Moreover, targeting APi1 is promising to enhance anti-tumor immunity and reverse ICB resistance. Citation Format: Erwei Song, Di Huang, Ruxin Wang. Tumor-derived APi1 inhibits antigen cross-presentation in dendritic cells and impairs anti-tumor immunity in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7241.