Abstract
Accumulating evidence suggests that tumor-infiltrating immune cells (TICs) in the tumor microenvironment (TME) serve as promising therapeutic targets. CXCL8 (IL-8) may also be a potential therapeutic target in cancer. CXCL8 is a potent chemotactic factor for neutrophils, myeloid-derived suppressor cells (MDSCs) and monocytes, which are considered immunosuppressive components in cancer-bearing hosts. Here, we identified the TME-related gene CXCL8 in a high-ImmuneScore population that contributed to better survival in colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA) database. An integrated gene profile and functional analysis of TIC proportions revealed that the dendritic cell (DC) activation markers CD80, CD83, and CD86 were positively correlated with CXCL8 expression, suggesting that CXCL8 may be functional as antitumor immune response status in the TME. The gene signature was further validated in independent GSE14333 and GSE38832 cohorts from the Gene Expression Omnibus (GEO). To test the differential contributions of immune and tumor components to progression, three CRC cell lines, CT26, MC38 and HCT116, were used. In vitro results suggested no significant growth or survival changes following treatment with an inhibitor of the CXCL8 receptor (CXCR1/2) such as reparixin or danirixin. In vivo treatment with danirixin (antagonists of CXCR2) promoted tumor progression in animal models established with CT26 cells. CXCR2 antagonism may function via an immune component, with CXCR2 antagonist treatment in mice resulting in reduced activated DCs and correlating with decreased Interferon gamma (IFN-γ) or Granzyme B expressed CD8+ T cells. Furthermore, CXCL8 induced DC migration in transwell migration assays. Taken together, our data suggested that targeting the CXCL8-CXCR2 axis might impede DC activation or recruitment, and this axis could be considered a favorable factor rather than a target for critical antitumor effects on CRC.
Highlights
Colorectal cancer (CRC) is the second most commonly diagnosed malignant tumor worldwide [1]
We further identified that the tumor microenvironment (TME)-related gene CXCL8 and a high ImmuneScore contributed to better survival in colorectal cancer (CRC) patients from the The Cancer Genome Atlas (TCGA) database
In order to further confirm the prognostic value of CXCL8 we discovered in TCGA cohort, we picked the corresponding probes of CXCL8 (202859_x_at) for survival test in GSE14333 and GSE38832 cohorts, which showed a better prognosis in patients with higher CXCL8 expression (Figure 2H, p=0.0244)
Summary
Colorectal cancer (CRC) is the second most commonly diagnosed malignant tumor worldwide [1]. CRC is usually characterized by a lengthy and very complicated process, including multiple steps leading to the normal epithelium’s malignant transformation into cancer cells. It usually involves numerous genetic changes that lead to multiple phenotypic changes [2]. Inflammation seems to be a key process that mediates the relationship and dual functions of cancer cells and immune cells in the tumor microenvironment (TME). Current studies have evaluated the expression of various cytokines, chemokines and their receptors in CRC [3]. Many studies have aimed to delineate the differential roles of cytokines, chemokines, and the TME in CRC relative to these components’ antitumor status through evaluation of subsets of immune cells
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