Unveiling the immunoregulatory role of interferon-induced transmembrane protein 2 through the JAK/STAT3/PDL1 pathway in gastric cancer

Programmed cell death ligand 1 (PDL1) has been implicated in immune evasion in various tumor types. The objective of this investigation was to assess the correlation between metastasis-associated interferon-induced transmembrane protein 2 (IFITM2) and PDL1, and explore their impact on tumor immunity in gastric Cancer (GC). The expression of IFITM2 and PDL1 in human GC tissues was initially evaluated using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, as well as immunohistochemistry (IHC). Subsequently, the relationship between IFITM2 and PDL1 was analyzed through Real-time quantitative PCR (RT-qPCR) and western blotting after Cell Transfection and inhibitor treatment in vitro. The role of IFITM2 and PDL1 in immune killing was further elucidated in both in vitro and in vivo settings. Our study revealed frequent overexpression of IFITM2 and PDL1 in GC. Notably, IFITM2 expression was significantly associated with lymphatic metastasis, clinical stage, and poor survival. Moreover, a positive correlation between PDL1 expression and IFITM2 expression in GC was identified. The activation of tumor-derived IFITM2 was found to enhance PDL1 expression via the JAK/STAT3 pathway in human GC cells (MKN28 and MKN45), leading to Apoptosis of Jurkat T cells. Furthermore, IFITM2 induced PDL1 expression in a xenograft mouse model of GC. Based on our findings, we propose that IFITM2 modulates PDL1 expression and tumor immunity through the JAK/STAT3 pathway in GC cells, highlighting the potential of IFITM2 as a therapeutic target for GC immunotherapy.

Gastric cancer; IFITM2; Immune escape; JAK/STAT3/ pathway; PDL1.