Spatial Evaluation and Prognostic Significance of V-Domain Immunoglobulin Suppressor of T-Cell Activation (VISTA) in Human Resectable Cervical Carcinoma: Implications for Immune Activation and Suppression.

Abstract

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a promising next-generation immune checkpoint target. This study investigated the distribution and clinical significance of VISTA expression in cervical carcinoma. Using a cohort of 290 patients from Sun Yat-sen Memorial Hospital, we assessed VISTA expression in tumor cells, endothelial cells, and immune cells (ICs) through immunohistochemistry, and found that it was expressed in tumor cells (18.6%), endothelial cells (38.3%), and ICs (100%). Higher infiltration of VISTA⁺ ICs was observed in the stromal region compared with that in the intratumoral region of resectable cervical carcinoma. Among the ICs, macrophages showed the highest VISTA expression compared with that by T cells and neutrophils. High intratumoral VISTA expression was an independent marker of favorable prognosis. Robust infiltration of VISTA⁺ ICs and CD8⁺ T cells in the tumor microenvironment correlated with the best clinical outcomes. In addition, in an independent cervical carcinoma cohort (n = 48), VISTA⁺ ICs in both intratumoral and stromal regions were positively associated with CD8⁺ T cells, CD103⁺ T cells, and effector molecules, such as granzyme B. Elevated VISTA expression was also associated with an enriched immunosuppressive profile, including Foxp3⁺ regulatory T cells and molecules such as TGF-β1, PD-1, LAG-3, TIM-3, and TIGIT. Moreover, multiplex staining and correlation analysis revealed a positive association between VISTA⁺ TGF-β1⁺ ICs and FOXP3⁺ regulatory T cells in tumor tissues. These findings establish a strong connection between intratumoral VISTA⁺ ICs and a regulatory immune contexture involving both activation and suppression signatures, with a skew toward activation dominance. Our study results suggest that VISTA can be employed as a potential prognostic biomarker for cervical carcinoma.