Potential Role of EBI3 in Gastric Cancer and Its Inductive Effects on T-Cell Exhaustion.

[BACKGROUND] Immunotherapy has achieved effective antitumor activity in advanced patients with gastric cancer (GC). However, the rate of response to immune checkpoint inhibitor therapy is disappointing, T-cell exhaustion may contribute to this phenomenon. EBI3 is an emerging immunosuppressive factor, and the association between EBI3 and T-cell exhaustion is not clear. In this study, we aimed to explore the expression of EBI3 in GC and reveal the function of EBI3 in T-cell exhaustion.

[STUDY DESIGN] The gene expression data and clinical data of patients with GC were downloaded from The Cancer Genome Atlas database to measure the expression of EBI3 in GC and explore the association between EBI3 and clinicopathologic features. Then, tumor specimens were collected, and immunohistochemistry was used to demonstrate the expression of EBI3 in GC tissues. Finally, we constructed a mouse model of orthotopic GC to examine the function of EBI3 in T-cell exhaustion.

[RESULTS] The data from The Cancer Genome Atlas database showed that EBI3 is highly expressed in GC and the expression of EBI3 is associated with pTNM stage. We analyzed the expression of EBI3 in GC tissues, the results showed that expression of EBI3 is associated with age, T stage, N stage, pTNM stage, and degree of differentiation. After constructing the mouse model of orthotopic GC, we found EBI3 can lead to an increase in proportion of CD8 + PD-1 + T cells and CD8 + LAG3 + T cells; meanwhile, the secretion of IL-2 was significantly decreased.

[CONCLUSIONS] Our study indicated that EBI3 is an important cytokine in the development of GC, and EBI3 may promote the development of GC by inducing T-cell exhaustion in the tumor microenvironment.