IRF5 is a novel regulator of CXCL13 expression in breast cancer that increases CXCR5+ B and T cell trafficking to the tumor (TUM7P.955)

Abstract

Abstract Clinical studies using predictive signatures have shown that a high immune signal from whole tumor expression profiles correlate with improved outcome in some cancers, including breast cancer. Factors regulating immune cell trafficking to the tumor, however, are not known. Utilizing MDA-MB-231 breast cancer cells grown in 3D culture, we examined whether intratumoral expression of interferon regulatory factor 5 (IRF5) regulates the profile of cytokines/chemokines expressed. Previous work has shown that IRF5 expression is lost in ~80% of all invasive ductal carcinomas examined. Using focused arrays, we found a number of cytokines/chemokines that were dysregulated between IRF5-positive and -negative MDA-MB-231 cells. CXCL13 was identified as a direct target of IRF5. Using tumor-conditioned media (TCM) from IRF5-positive and -negative cells, we found a significant increase in B and T cell trafficking to TCM from IRF5-positive cells. Subset analysis revealed that primary CXCR5+ B and T cells showed significantly reduced migration to IRF5-negative TCM or IRF5-positive TCM depleted of CXCL13. CXCR5 is the primary receptor for CXCL13. Analysis of human breast tumor tissues revealed a positive correlation between IRF5 and CXCL13 expression providing clinical relevance to this study. Data support that IRF5 directly regulates a network of genes that shapes a tumor immune response and may serve as a novel prognostic marker for chemotherapy and immunotherapy response.