36P - FOXP1 suppresses chemokine genes critical for TIL migration and function in breast tumors

Date 04 May 2017
Event IMPAKT 2017
Session Welcome reception and Poster Walk
Topics Biomarkers
Breast Cancer
Translational Research
Presenter Pushpamali De Silva
Authors P. De Silva1, S. Garaud1, C. Solinas1, A. Boisson1, A. De Wind2, G. Van den Eyden3, C. Naveaux1, D. Hugues4, M. Piccart-Gebhart5, K. Willard-Gallo1
  • 1Molecular Immunology Unit, Institut Jules Bordet, 1000 - Brussels/BE
  • 2Department Of Pathology, Institut Jules Bordet, 1000 - Brussels/BE
  • 3Centre, General Hospital Sint Augustinus, Wilrijk/BE
  • 4Flow Cytometry Facility, Institut Jules Bordet, Université Libre de Bruxelles, 1000 - Bruxelles/BE
  • 5Department Of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, 1000 - Bruxelles/BE

Abstract

Body

TIL are linked to better clinical outcomes in all subtypes of breast cancer (BC). High TIL infiltration is characterized by their organized into tertiary lymphoid structures (TLS). Factors regulating the successful infiltration of immune cells and their organization in TLS are currently unknown. The forkhead box protein 1 (FOXP1), a transcription factor, is shown to be abnormally expressed in a variety of human tumors including BC. However its role in BC tumor progression is inconsistent. Thus we aimed to study FOXP1 mediated regulation of TIL in BC. FOXP1 gene/protein analysis among BC subtypes showed it’s more enriched in estrogen receptor (ER) positive tumors (Luminal A/B) which are known to be low infiltrated and repressed in highly infiltrated ER- tumors (HER2+/triple negative). Moreover, high FOXP1 expression in a cohort of untreated primary breast tissues was significantly associated with a lower percentage of TIL and number of TLS compared to FOXP1 lowtumors. This led us to investigate the impact of FOXP1 on specific cytokines/chemokines involved in TIL recruitment and/or TLS formation in breast tissues. Silencing FOXP1 in MCF7 (FOXP1high) or upregulating in MDA-MB-231 (FOXP1low) BC cell lines followed by analysis using a human cytokine/chemokine gene array, we found FOXP1 repression upregulating array of chemokines/cytokines mainly impacting T and B cell migration and function while overexpression repressing most of these molecules. Analyzing major T and B cell chemokines/cytokines genes in FOXP1low and FOXP1high breast tumors revealed that FOXP1high tumors having a significant decrease in CXCL9, CXCL10, CXCL11, CXCL13, CX3CL, CCL20, IL2, IL21, Granzyme B and Interferon gamma. Also FOXP1high tumors had high levels of immunosuppressive cytokines; IL10 and TGFβ. When we performed a lymphocyte migration assay using FOXP1low and FOXP1high tumor supernatants (SN) from primary tumors revealed a significant decrease in total number of lymphocytes, B cells, T helpers and cytotoxic T cells migrated towards FOXP1hi SN. Our data suggest that FOXP1 could play a critical role in establishing effective anti-tumor immune responses by negative regulation of TIL via suppression of cytokines/chemokines in breast tumors

Clinical trial identification