FOXP1 negatively regulates tumor infiltrating lymphocyte migration in human breast cancer

Abstract

BackgroundFOXP1, a transcriptional regulator of lymphocyte development, is abnormally expressed in some human tumors. This study investigated FOXP1-mediated regulation of tumor infiltrating lymphocytes (TIL) in untreated primary breast cancer (BC).MethodsFOXP1 expression was analyzed in tissues from primary untreated breast tumors, BC cell lines and the METABRIC gene expression BC dataset. Cytokine and chemokine expression and lymphocyte migration in response to primary tumor supernatants (SN) was compared between FOXP1hi and FOXP1lo primary BC.FindingFOXP1 expression was higher in estrogen receptor positive compared to negative BC. FOXP1hi tumors were significantly associated with lower TIL and fewer tertiary lymphoid structures (TLS) compared to FOXP1lo BC. Silencing FOXP1 in BC cell lines positively impacted cytokine and chemokine expression with the inverse effect associated with overexpression. CXCL9, CXCL10, CXCL11, CXCL13, CX3CL, CCL20, IL2, IL21, GZMB and IFNG expression decreased while IL10 and TGFβ increased in FOXP1hi compared to FOXP1lo primary BC. Lymphocyte migration using primary BC supernatants detected decreased mobility toward FOXP1hi supernatants. FOXP1lo BC expresses higher levels of chemokines driving TIL migration. The METABRIC gene expression dataset analysis show FOXP1 expression is associated with unfavorable BC outcomes.InterpretationThese data identify FOXP1 as an important negative regulator of immune responses in BC via its regulation of cytokine and chemokine expression.FundBelgian Fund for Scientific Research (FNRS 3.4513.12F) and Opération Télévie (7.4636.13F and 7.4609.15F), Fonds J.C. Heuson and Fonds Lambeau-Marteaux.

CRISPR/Cas9-Mediated Foxp1 Silencing Restores Immune Surveillance in an Immunocompetent A20 Lymphoma Model

“…This is also consistent with T-cell activation signatures being affected by FOXP1 silencing in human DLBCL cell lines (9). It is also possible that Foxp1 depletion may improve lymphocyte migration into the tumor microenvironment, as is the case in breast cancer where FOXP1 has recently been identified as a negative regulator of tumor infiltrating lymphocyte migration (43). However, preliminary ex vivo immunohistochemical analysis of harvested A20 tumors only found reduced numbers of CD3 + and CD8 + T cells in the Foxp1 exon 7 targeted tumors (data not shown), suggesting that reduced T-cell infiltration may not explain the common phenotype shared by both A20 clones.…”

Tumor-infiltrating B cells signal functional humoral immune responses in breast cancer

“…69). Our laboratory recently demonstrated that the transcription factor FOXP1 is an important negative regulator of immune cell migration in BC via its impact on tumor cell cytokine and chemokine expression (70). Further, we found that CXCL13-producing T FH (named T FH X13) TIL promote local memory TIL-B differentiation and are potentially an early trigger of TLS formation in BC (12).…”

G9a regulates tumorigenicity and stemness through genome-wide DNA methylation reprogramming in non-small cell lung cancer

“…Forkhead Box P1 (FOXP1) belongs to the forkhead box transcription factor family, and has known to have dual roles as a tumor suppressor gene and as an oncogene in multiple cancer types [64,65]. FOXP1 deletions are found in squamous cell carcinomas of the lung, and expression of FOXP1 is associated with breast cancer development in poor prognosis in patients [4,64,66].…”