ABSTRACT: Campylobacter concisus upregulates PD-L1 expression in IFN-gamma sensitized intestinal epithelial cells and induces cell death in esophageal epithelial cells
Project description:PD-L1 suppresses host immunity and promotes tumor growth. We investigated how IFN-? regulates PD-L1 in the ovarian cancer microenvironment. In clinical samples, the number of stromal CTLs in peritoneally disseminated tumors was correlated with PD-L1 expression on the tumor cells, and the lymphocyte number was significantly related to the IFN-? signature score. In mouse models, PD-L1 was induced in peritoneal disseminated tumors, where lymphocytes were prominent, but not in subcutaneous tumors. Depleting IFNGR1 resulted in lower PD-L1 expression and longer survival in peritoneal dissemination model. Injection of IFN-? into subcutaneous tumors increased PD-L1 expression and tumor size, and PD-L1 depletion abrogated tumor growth. These data suggest that IFN-? works as a tumor progressor through PD-L1 induction. The source of IFN-? in ovarian cancer microenvironment and its biological effect to the tumor cells is unclear. The immortalized human ovarian surface epithelial cell line, HOSE-E7/hTERT (HOSE) was treated with IFN-? and expression microarray analysis was performed, and probes showing significantly higher values in IFN-?-added group were termed “IFN-? signature genes (295 probes)”. We then applied this signature to our ovarian cancer microarray data, which included 75 ovarian cancer clinical samples, by means of ss-GSEA. IFN-? signature score was strongly correlated to the number of infiltrating CD4-positive or CD8-positive lymphocytes in the tumors. These data suggest that the IFN-? in the ovarian cancer microenvironment is derived from lymphocytes, and an IFN-?-rich microenvironment is strongly correlated to a lymphocyte-rich microenvironment. Genome-wide transcriptional changes in human ovarian cancer tissue were observed in different tumor immunological microenvironment.
Project description:PD-L1 suppresses host immunity and promotes tumor growth. We investigated how IFN-γ regulates PD-L1 in the ovarian cancer microenvironment. In clinical samples, the number of stromal CTLs in peritoneally disseminated tumors was correlated with PD-L1 expression on the tumor cells, and the lymphocyte number was significantly related to the IFN-γ signature score. In mouse models, PD-L1 was induced in peritoneal disseminated tumors, where lymphocytes were prominent, but not in subcutaneous tumors. Depleting IFNGR1 resulted in lower PD-L1 expression and longer survival in peritoneal dissemination model. Injection of IFN-γ into subcutaneous tumors increased PD-L1 expression and tumor size, and PD-L1 depletion abrogated tumor growth. These data suggest that IFN-γ works as a tumor progressor through PD-L1 induction. The source of IFN-γ in ovarian cancer microenvironment and its biological effect to the tumor cells is unclear. The immortalized human ovarian surface epithelial cell line, HOSE-E7/hTERT (HOSE) was treated with IFN-γ and expression microarray analysis was performed, and probes showing significantly higher values in IFN-γ-added group were termed “IFN-γ signature genes (295 probes)”. We then applied this signature to our ovarian cancer microarray data, which included 75 ovarian cancer clinical samples, by means of ss-GSEA. IFN-γ signature score was strongly correlated to the number of infiltrating CD4-positive or CD8-positive lymphocytes in the tumors. These data suggest that the IFN-γ in the ovarian cancer microenvironment is derived from lymphocytes, and an IFN-γ-rich microenvironment is strongly correlated to a lymphocyte-rich microenvironment.
Project description:Lymphatic endothelial cells (LEC) comprise lymphatic vessels that guide immune cells to lymph nodes (LN) and form the subcapsular sinus and cortical and medullary lymphatic structures of the LN. During an active immune response the lymphatics remodel to accommodate the influx of immune cells from the tissue. In this study we determined that a TSS motif within the cytoplasmic domain of programmed death ligand 1 (PD-L1), expressed by LECs in the LN, participates in lymphatic remodeling during inflammation. Mutation of the TSS motif to AAA in the cytoplasmic domain of PD-L1 does not affect surface expression of PD-L1 but instead causes defects in LN cortical and medullary lymphatic organization following Poly I:C in vivo. Supporting this observation, in vitro treatment of the LEC cell line, SVEC4-10, with the cytokines TNF alpha and IFN alpha significantly impeded SVEC4-10 movement in the presence of the TSS-AAA cytoplasmic mutation. The cellular movement defects coincided with reduced F-actin polymerization, consistent with differences previously found in dendritic cells. Here, in addition to loss of actin polymerization we define STAT3 and Paxillin as important binding partners to PD-L1. STAT3 and Paxillin were previously demonstrated to be important at focal adhesions for cellular motility. We further demonstrate the TSS-AAA motif mutation of PD-L1 reduced the amount of pSTAT3 and Paxillin bound to PD-L1 both before and after exposure to TNF alpha and IFN alpha. Together, these findings highlight PD-L1 as an important component of a membrane complex that is involved in cellular motility which leads to defects in lymphatic organization.
