VISTA/CTLA4/PD1 在肿瘤细胞上的共表达赋予高级别浆液性卵巢癌有利的免疫微环境和更好的预后

INTRODUCTION: Immunotherapy by blocking immune checkpoints programmed death/ligand (PD1/PDL1) and cytotoxic T-lymphocyte-associated protein 4(CTLA4) has emerged as new therapeutic targets in cancer. However, their efficacy has been limited due to resistance. A new- checkpoint V-domain Ig-containing suppressor of T cell activation (VISTA) has appeared, but the use of its inhibition effect in combination with antibodies targeting PDL1/PD1and CTLA4 has not been reported in ovarian cancer. METHODS: In this study, we investigated the expressions of VISTA, CTLA4, and PDL1 using immunohistochemistry (IHC)on 135 Formalin-Fixed Paraffin-Embedded (FFPE)tissue samples of High-grade serous carcinoma (HGSOC). VISTA, CTLA4, PDL1, PD1, CD8, CD4, and FOXP3 mRNA extracted from 429 patients with ovarian cancer in the Cancer Genome Atlas (TCGA) database was included as a validation cohort. Correlations between these checkpoints, tumor-infiltrating- lymphocytes (TILs), and survival were analyzed. RESULTS AND DISCUSSION: CTLA4 was detectable in 87.3% of samples, VISTA in 64.7%, PD1 in 56.7%, and PDL1 in 48.1%. PDL1 was the only tested protein associated with an advanced stage ( p =0.05). VISTA was associated with PDL1, PD1, and CTLA4 expressions ( p =0.005, p =0.001, p =0.008, respectively), consistent with mRNA level analysis from the TCGA database. Univariate analyses showed only VISTA expression ( p =0.04) correlated with overall survival (OS). Multivariate analyses showed that VISTA expression ( p =0.01) and the coexpression of VISTA + /CTLA4 + /PD1 + ( p =0.05) were associated with better OS independently of the clinicopathological features. Kaplan-Meier analysis showed that the coexpression of the VISTA + /CTLA4 + /PDL1 + and VISTA + /CTLA4 + /PD1 + checkpoints on tumor cells (TCs)were associated with OS (p=0.02 and p <0.001; respectively). VISTA + /CTLA4 + /PD1 + in TCs and CD4 + /CD8 + TILswere associated with better 2-yer OS. This correlation may refer to the role of VISTA as a receptor in the TCs and not in the immune cells. Thus, targeting combination therapy blocking VISTA, CTLA4, and PD1 could be a novel and attractive strategy for HGSOC treatment, considering the ambivalent role of VISTA in the HGSOC tumor cells.