title: IRF5 is a novel regulator of CXCL13 expression in breast cancer that regulates CXCR5(+) B- and T-cell trafficking to tumor-conditioned media.
abstract: Clinical studies using prognostic and predictive signatures have shown that an immune signal emanating from whole tumors reflects the level of immune cell infiltration--a high immune signal linked to improved outcome. Factors regulating immune cell trafficking to the tumor, however, are not known. Previous work has shown that expression of interferon regulatory factor 5 (IRF5), a critical immune regulator, is lost in ~80% of invasive ductal carcinomas examined. We postulated that IRF5-positive and -negative breast tumors would differentially regulate immune cell trafficking to the tumor. Using a focused tumor inflammatory array, differences in cytokine and chemokine expression were examined between IRF5-positive and -negative MDA-MB-231 cells grown in three-dimensional culture. A number of cytokines/chemokines were found to be dysregulated between cultures. CXCL13 was identified as a direct target of IRF5 resulting in the enhanced recruitment of B and T cells to IRF5-positive tumor-conditioned media. The ability of IRF5 to regulate mediators of cell migration was confirmed by enzyme-linked immunosorbent assay, chromatin immunoprecipitation assay, small interfering RNA knockdown and immunofluorescence staining of human breast tumor tissues. Analysis of primary immune cell subsets revealed that IRF5 specifically recruits CXCR5(+) B and T cells to the tumor; CXCR5 is the receptor for CXCL13. Analysis of primary breast tumor tissues revealed a significant correlation between IRF5 and CXCL13 expression providing clinical relevance to the study. Together, these data support that IRF5 directly regulates a network of genes that shapes a tumor immune response and may, in combination with CXCL13, serve as a novel prognostic marker for antitumor immunity.
authors.affiliation: 1] Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, NJ, USA [2] Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: Erica Maria
authors.initials: EM
authors.lastname: Pimenta
authors.affiliation: 1] Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, NJ, USA [2] Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: Saurav
authors.initials: S
authors.lastname: De
authors.affiliation: 1] Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, NJ, USA [2] Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Weiss
authors.affiliation: 1] Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, NJ, USA [2] Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Feng
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hall
authors.affiliation: Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kilic
authors.affiliation: 1] Department of Molecular Biology, Biochemistry & Physics, Rutgers University, Piscataway, NJ, USA [2] Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
authors.forename: Gyan
authors.initials: G
authors.lastname: Bhanot
authors.affiliation: Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.
authors.forename: Shridar
authors.initials: S
authors.lastname: Ganesan
authors.affiliation: Department of Medical Microbiology, Immunology and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Ran
authors.affiliation: 1] Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers Biomedical and Health Sciences, Newark, NJ, USA [2] Rutgers Biomedical and Health Sciences, New Jersey Medical School-Cancer Center, UMDNJ, Newark, NJ, USA.
authors.forename: Betsy J
authors.initials: BJ
authors.lastname: Barnes
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001943:Breast Neoplasms / Q000276:immunology*; D002465:Cell Movement; D054382:Chemokine CXCL13 / Q000235:genetics / Q000378:metabolism; D017077:Culture Media, Conditioned; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D054380:Receptors, CXCR5 / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D019076:Transgenes / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: C095085:CXCR5 protein, human; D054382:Chemokine CXCL13; D017077:Culture Media, Conditioned; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D054380:Receptors, CXCR5