Abstract 921: SOX11-mediated antigen presentation suppression: A mechanism of immune evasion in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is an aggressive subtype with no targeted therapies and limited response to immunotherapy. TNBC evades immune surveillance by repressing antigen presentation machinery (APM) genes, reducing MHC Class I expression. Using bioinformatics, we identified SOX11 as a potential transcriptional regulator associated with APM suppression and immune evasion in TNBC. Methods: Gene expression data from basal breast cancer (BRCA) tumors (n = 189) in TCGA and cancer cell lines (n = 1, 189) in DepMap were analyzed. Spearman correlation coefficients were used to evaluate associations between a T-cell infiltration signature (e.g., CD3, CD8) and an APM signature (e.g., TAP1, TAP2, B2M, HLA-ABC). SOX11 was prioritized as it was strongly negatively correlated with both signatures. Differential expression analysis of SOX11-overexpression (OE) and knockdown (KD) datasets confirmed potential downstream targets, including MEX3A. To validate, SOX11 KD was performed in CAL-148 cells (high level of endogenous SOX11) using siRNA for 96 hours. Western blot assessed SOX11 and MEX3A protein levels, while flow cytometry measured surface MHC Class I (HLA-ABC) expression. Results: SOX11 was strongly inversely correlated (rho < -0.4, adjusted p < 0.01) with APM and T-cell infiltration signatures in basal BRCA and DepMap datasets. In basal BRCA tumors, SOX11 expression was enriched in T-cell cold tumors compared to T-cell hot tumors (p < 0.01). Reanalysis of SOX11-modulated datasets (KD and OE) confirmed APM-suppressive downstream targets, with MEX3A showing a strong co-expression pattern (Spearman p<0.05). SOX11 KD in CAL-148 cells significantly reduced MEX3A protein levels and increased surface HLA-ABC expression. These findings suggest that SOX11 represses antigen presentation pathways, contributing to immune evasion in TNBC. Conclusions: SOX11 suppresses HLA-A/B/C expression and may contribute to immune evasion in TNBC. Its high expression in T-cell cold tumors and its regulation of APM targets, including MEX3A, highlight its potential as a therapeutic target. Targeting SOX11 could restore antigen presentation, promote immune recognition, and enhance immunotherapy responses in TNBC. Citation Format: Salomat Abdulkhuseynova, Ashok Pullikuth, Lance Miller, Shay Soker. SOX11-mediated antigen presentation suppression: A mechanism of immune evasion in triple-negative 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 921.