Abstract PS4-10-05: Dsc3 suppresses the ccl21-pdc-treg axis to reprogram immunosuppressive microenvironment and potentiate immunotherapy in triple-negative breast cancer

Abstract The emergence of immunotherapy has revolutionized cancer treatment, particularly with the exploration of PD-1/PD-L1 checkpoints. However, its efficacy in triple-negative breast cancer remains limited. In this study, RNA-Seq analysis was performed on baseline samples from patients in the phase II single-arm clinical trial, TREND. By integrating data from public immunotherapy cohorts, we aimed to identify potential biomarkers. Desmocollin 3 (DSC3) was identified due to its strong association with pathological complete response. In animal models, DSC3-overexpressing tumors showed increased sensitivity to anti-PD-1 therapy, which was dependent on host-specific immunity. Tumor-infiltrating lymphocytes and draining lymph nodes exhibited an increased proportion of T cells with enhanced cytotoxic functions, including IFN-gamma and TNF-alpha production, which are critical for anti-PD-1 therapy efficacy. To explore how DSC3 enhances T cell cytotoxicity, we investigated dendritic cell subsets and other myleoids cell subsets. We found reduced plasmacytoid dendritic cells (pDCs) in DSC3-overexpressing tumors. Since pDCs recruitment is mediated by CCL21.e.g., we further examined its secretion to understand why pDCs were reduced. DSC3 overexpression led to decreased CCL21 secretion, impairing pDC recruitment and mitigating their interaction with regulatory T cells, which alleviated the local immune-suppressive tumor microenvironment and promoted T cell infiltration and cytotoxic function. To investigate the mechanism of reduced CCL21 secretion, we explored the relationship between DSC3 and the transcription factor SOX2. Molecular experiments, including ChIP, suggested that DSC3 mRNA competes with transcription factor SOX2, inhibiting its transcriptional activity on CCL21, in nucleus. Overall, our study highlights DSC3 as a potential biomarker for patient stratification in anti-PD-1 therapy and identifies novel immune system targets aimed at improving immunotherapy efficacy. Citation Format: Y. Wang, Y. Xu. Dsc3 suppresses the ccl21-pdc-treg axis to reprogram immunosuppressive microenvironment and potentiate immunotherapy 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 PS4-10-05.