CXCL8 Up-Regulated LSECtin through AKT Signal and Correlates with the Immune Microenvironment Modulation in Colon Cancer

SIMPLE SUMMARY: Patients with high expression of CXCL8 are not sensitive to immune checkpoint inhibitors (ICIs) treatment, but the mechanism is unclear. LSECtin is the immune checkpoint ligand of LAG3, and is considered as an important factor of ICIs resistance. This study confirmed the role of CXCL8 and LSECtin in immune microenvironment modulation of colon cancer. The expression of CXCL8 is positively correlated with more than 40 immune checkpoints. CXCL8 could up-regulate LSECtin through AKT signal and promoted the proliferation and invasion ability of colon cancer. These results may be important reasons for the primary drug resistance of ICIs in colon cancer. ABSTRACT: Background: The role of CXCL8 and LSECtin in colon cancer liver metastasis and immune checkpoint inhibitors (ICIs) treatment effect were widely recognized. However, the regulatory role of CXCL8 on LSECtin is still unclear. Methods: The expression of CXCL8 or LSECtin was analyzed by TCGA database, and verified by GES110225 and clinical samples. The relationship between the expression of CXCL8 or LSECtin and immune cells infiltration, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology (GO) items, stromal score, Estimation of STromal and Immune cells in MAlignant Tumours (ESTIMAT) immune score, tumor mutation burden (TMB), mismatch repair gene and immune checkpoints expression were analyzed by Spearman. The effects of CXCL8 on LSECtin expression, proliferation, and invasion ability were clarified by recombinant CXCL8 or CXCL8 interfering RNA. Results: In colon cancer, the expression of CXCL8 was higher, but LSECtin was lower than that in normal mucosa. The expression of CXCL8 or LSECtin was significantly positively correlated with immune cells infiltration, stromal score, ESTIMATE immune score, TMB, and immune checkpoints expression. The expression of LSECtin was closely related to the cytokine-cytokine receptor interaction pathway and response of chemokine function, such as CXCL8/CXCR1/2 pathway. There was a significant positive correlation between the expression of CXCL8 and LSECtin in colon cancer. CXCL8 up-regulated LSECtin through AKT signal and promoted the proliferation and invasion ability of colon cancer. Conclusions: CXCL8 up-regulated LSECtin by activating AKT signal and correlated with the immune microenvironment modulation in colon cancer.