High IRF8 expression correlates with CD8 T cell infiltration and is a predictive biomarker of therapy response in ER-negative breast cancer

Breast Cancer Research

Elmer Fernández¹  Emiliano Roselli²  Lucia Boffelli²  Paula Araya²  Mariana Maccioni²  Jeremías Dutto²  Lisa M. Coussens³  Courtney Betts³  Darío Rocha⁴  Nicolas G. Nuñez⁵  Cecilia Ditada⁶  Verónica Grupe⁶  Maribel Nicola⁶  Gerardo Gatti⁷ 

[1] Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina;CIDIE-CONICET, Universidad Católica de Córdoba, Córdoba, Argentina;Departamento de Bioquímica Clínica, Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, 5000, Córdoba, Argentina;Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA;Facultad de Ciencias Exactas, Físicas y Naturales, Universidad Nacional de Córdoba, Córdoba, Argentina;Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland;Laboratorio de Investigación en Cáncer, Fundación para el progreso de la Medicina, X5000EMS, Córdoba, Argentina;Laboratorio de Investigación en Cáncer, Fundación para el progreso de la Medicina, X5000EMS, Córdoba, Argentina;Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina;

关键词: Breast cancer;    IRF8;    DNA methylation;    Predictive marker;    Tumor-infiltrate;   

DOI  :  10.1186/s13058-021-01418-7

来源: Springer

【 摘 要 】

BackgroundCharacterization of breast cancer (BC) through the determination of conventional markers such as ER, PR, HER2, and Ki67 has been useful as a predictive and therapeutic tool. Also, assessment of tumor-infiltrating lymphocytes has been proposed as an important prognostic aspect to be considered in certain BC subtypes. However, there is still a need to identify additional biomarkers that could add precision in distinguishing therapeutic response of individual patients. To this end, we focused in the expression of interferon regulatory factor 8 (IRF8) in BC cells. IRF8 is a transcription factor which plays a well-determined role in myeloid cells and that seems to have multiple antitumoral roles: it has tumor suppressor functions; it acts downstream IFN/STAT1, required for the success of some therapeutic regimes, and its expression in neoplastic cells seems to depend on a cross talk between the immune contexture and the tumor cells.The goal of the present study was to examine the relationship between IRF8 with the therapeutic response and the immune contexture in BC, since its clinical significance in this type of cancer has not been thoroughly addressed.MethodsWe identified the relationship between IRF8 expression and the clinical outcome of BC patients and validated IRF8 as predictive biomarker by using public databases and then performed in silico analysis. To correlate the expression of IRF8 with the immune infiltrate in BC samples, we performed quantitative multiplex immunohistochemistry.ResultsIRF8 expression can precisely predict the complete pathological response to monoclonal antibody therapy or to select combinations of chemotherapy such as FAC (fluorouracil, adriamycin, and cytoxan) in ER-negative BC subtypes. Analysis of immune cell infiltration indicates there is a strong correlation between activated and effector CD8+ T cell infiltration and tumoral IRF8 expression.ConclusionsWe propose IRF8 expression as a potent biomarker not only for prognosis, but also for predicting therapy response in ER-negative BC phenotypes. Its expression in neoplastic cells also correlates with CD8+ T cell activation and infiltration. Therefore, our results justify new efforts towards understanding mechanisms regulating IRF8 expression and how they can be therapeutically manipulated.

【 授权许可】

CC BY