AIF1 Regulates the Progression of Esophageal Squamous Cell Carcinoma Through Negative Regulation of Immune T Cell Efflux Function by TIGIT Signal

Background: Esophageal Cancer stands as one of the most aggressive and lethal malignancies among digestive tract tumors.

Aims: This study aimed to explore whether AIF1 regulated immune infiltration in esophageal Cancer and its association with TIGIT.

Methods: AKR cells transfected with an AIF1 overexpression vector were subcutaneously injected into mice. Additionally, mice were treated with a TIGIT monoclonal antibody. Tumor growth was monitored, and the proportions of different T cell subsets in tumor tissues were detected. AKR cells transfected with AIF1 and Treg cells transfected with TIGIT were co-cultured. Cell viability was assessed using the CCK-8 assay. The expression levels of immune infiltration-related markers (FOXP3, Tim3, and IL-6) were detected by ELISA or Western blotting.

Results: Overexpression of AIF1 combined with TIGIT mAb treatment inhibited tumor growth. This combination promoted the expression of CD3⁺ and IFN-γ (markers of effector T cells) and suppressed the expression of FOXP3 and Tim3 (markers related to immune suppression). In the AIF/TIGIT-treated group, the expressions of pro-inflammatory cytokines (IFN-γ, IL-6, and TNF-α) were up-regulated, while the expressions of anti-inflammatory cytokines (TNF-β and IL-10) were down-regulated. AIF/TIGIT treatment significantly inhibited the expression of immune-specific factors PD-1, FOXP3 in the tissue cells. When TIGIT-overexpressing T cells were co-cultured with Cancer cells, cell viability was lower compared to the group with AIF1 overexpression alone. Notably, the group with both AIF1 overexpression and TIGIT overexpression exhibited the lowest cell viability. Under conditions of AIF1 overexpression and TIGIT overexpression, the levels of LDH, TNF-α, and IFN-γ in Cancer cells were also the lowest, indicating a synergistic effect on modulating cell function and cytokine secretion.

Conclusions: AIF1 may regulate the progression of esophageal squamous cell carcinoma by negatively modulating the efflux function of immune T cells via the TIGIT signaling pathway.

AIF1; Esophageal squamous cell carcinoma; FOXP3; Immunoinfiltration; TIGIT.