Osteoglycin-induced VEGF Inhibition Enhances T Lymphocytes Infiltrating in Colorectal Cancer.

ABSTRACT

BACKGROUND: OGN could modify tissue inflammation and immune response via local and circulating innate immune cells, which was suggestive of a reciprocal relationship between OGN and T cell infiltration in cancer. Hence, we aim to measure the OGN expression patterns and immune cells response in colorectal cancer(CRC). METHODS: This study enrolled three independent sets of patients from TCGA and the Fudan University Shanghai Cancer Center(FUSCC). The effect of OGN on T cell infiltration and the mechanism were examined in vitro and in vivo. FINDINGS: Tumor OGN expression levels were positively associated with CD3, CD8, and PTPRC expressions in the training and testing sets from TCGA, respectively. In validation set from FUSCC, OGN expression level also paralleled positively with CD8+ cell density in colorectal cancer tissue (p < .001). For a unit decrease in outcome quartile categories, multivariable OR in the lowest (vs highest) OGN expression was 0.17 (95% CI 0.08-0.33). Consistently, immunofluorescence validated that OGN was preferentially expressed with CD8+ cells in both normal epithelium and cancer tissue. Xenograft tumors arising from MC38 cells with OGN-over-expression displayed a significant increase in CD8+ cells recruitment. Hence, high expression of OGN was associated with a profound longer survival (P = .009). In mechanism, elevated OGN expression inhibited the activation of the transcriptional genes HIF-1α in CRC cells, then significantly impeded the expression of VEGF. As a result of this, T cell tumor infiltration was reduced. INTERPRETATION: OGN expression is positively associated with CD8+ cell density in colorectal cancer tissue, suggesting a possible influence of OGN expression on tumor reactive T cells in the tumor niche. FUND No.