VISTA/CTLA4/PD1 Coexpression on Tumor Cells Confers a Favorable Immune Microenvironment and Better Prognosis in High-grade Serous Ovarian Carcinoma

Overview

Journal Front Oncol

Specialty Oncology

Date 2024 Apr 18

PMID 38634058

Authors

Aida Jlassi

Rim Rejaibi

Maroua Manai

Ghada Sahraoui

Fatma Zahra Guerfali

Lamia Charfi

Amel Mezlini

Mohamed Manai

Karima Mrad

Raoudha Doghri

Affiliations

Soon will be listed here.

Abstract

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 (=0.05). VISTA was associated with PDL1, PD1, and CTLA4 expressions (=0.005, =0.001, =0.008, respectively), consistent with mRNA level analysis from the TCGA database. Univariate analyses showed only VISTA expression (=0.04) correlated with overall survival (OS). Multivariate analyses showed that VISTA expression (=0.01) and the coexpression of VISTA/CTLA4/PD1 (=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 <0.001; respectively). VISTA/CTLA4/PD1 in TCs and CD4/CD8TILswere 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.

References

Theodoraki M, Yerneni S, Hoffmann T, Gooding W, Whiteside T . Clinical Significance of PD-L1 Exosomes in Plasma of Head and Neck Cancer Patients. Clin Cancer Res. 2017; 24(4):896-905. PMC: 6126905. DOI: 10.1158/1078-0432.CCR-17-2664. View

Kakavand H, Jackett L, Menzies A, Gide T, Carlino M, Saw R . Negative immune checkpoint regulation by VISTA: a mechanism of acquired resistance to anti-PD-1 therapy in metastatic melanoma patients. Mod Pathol. 2017; 30(12):1666-1676. DOI: 10.1038/modpathol.2017.89. View

Muller S, Lai W, Adusumilli P, Desmeules P, Frosina D, Jungbluth A . V-domain Ig-containing suppressor of T-cell activation (VISTA), a potentially targetable immune checkpoint molecule, is highly expressed in epithelioid malignant pleural mesothelioma. Mod Pathol. 2019; 33(2):303-311. PMC: 8366498. DOI: 10.1038/s41379-019-0364-z. View

Boger C, Behrens H, Kruger S, Rocken C . The novel negative checkpoint regulator VISTA is expressed in gastric carcinoma and associated with PD-L1/PD-1: A future perspective for a combined gastric cancer therapy?. Oncoimmunology. 2017; 6(4):e1293215. PMC: 5414883. DOI: 10.1080/2162402X.2017.1293215. View

Liao H, Zhu H, Liu S, Wang H . Expression of V-domain immunoglobulin suppressor of T cell activation is associated with the advanced stage and presence of lymph node metastasis in ovarian cancer. Oncol Lett. 2018; 16(3):3465-3472. PMC: 6096210. DOI: 10.3892/ol.2018.9059. View

Antomarchi J, Ambrosetti D, Cohen C, Delotte J, Chevallier A, Karimdjee-Soilihi B . Immunosuppressive Tumor Microenvironment Status and Histological Grading of Endometrial Carcinoma. Cancer Microenviron. 2019; 12(2-3):169-179. PMC: 6937359. DOI: 10.1007/s12307-019-00225-1. View

Kuklinski L, Yan S, Li Z, Fisher J, Cheng C, Noelle R . VISTA expression on tumor-infiltrating inflammatory cells in primary cutaneous melanoma correlates with poor disease-specific survival. Cancer Immunol Immunother. 2018; 67(7):1113-1121. PMC: 11028124. DOI: 10.1007/s00262-018-2169-1. View

Jlassi A, Manai M, Morjen M, Sahraoui G, Elasmi Allal M, ELBini-Dhouib I . VISTA+/CD8+ status correlates with favorable prognosis in Epithelial ovarian cancer. PLoS One. 2023; 18(3):e0278849. PMC: 10035885. DOI: 10.1371/journal.pone.0278849. View

Zong L, Zhou Y, Zhang M, Chen J, Xiang Y . VISTA expression is associated with a favorable prognosis in patients with high-grade serous ovarian cancer. Cancer Immunol Immunother. 2019; 69(1):33-42. PMC: 6949319. DOI: 10.1007/s00262-019-02434-5. View

10.

Birnbaum D, Finetti P, Lopresti A, Gilabert M, Poizat F, Turrini O . Prognostic value of PDL1 expression in pancreatic cancer. Oncotarget. 2016; 7(44):71198-71210. PMC: 5342072. DOI: 10.18632/oncotarget.11685. View

11.

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G . The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2014; 26(2):259-71. PMC: 6267863. DOI: 10.1093/annonc/mdu450. View

12.

He H, Gao Y, Fu J, Zhou Q, Wang X, Bai B . VISTA and PD-L1 synergistically predict poor prognosis in patients with extranodal natural killer/T-cell lymphoma. Oncoimmunology. 2021; 10(1):1907059. PMC: 8032243. DOI: 10.1080/2162402X.2021.1907059. View

13.

Jo J, Kim M, Choi Y, Kim H, Kim J, Chae S . Expression of programmed cell death 1 and programmed cell death ligand 1 in extranodal NK/T-cell lymphoma, nasal type. Ann Hematol. 2016; 96(1):25-31. DOI: 10.1007/s00277-016-2818-4. View

14.

Lines J, Sempere L, Broughton T, Wang L, Noelle R . VISTA is a novel broad-spectrum negative checkpoint regulator for cancer immunotherapy. Cancer Immunol Res. 2014; 2(6):510-7. PMC: 4085258. DOI: 10.1158/2326-6066.CIR-14-0072. View

15.

Kondo Y, Ohno T, Nishii N, Harada K, Yagita H, Azuma M . Differential contribution of three immune checkpoint (VISTA, CTLA-4, PD-1) pathways to antitumor responses against squamous cell carcinoma. Oral Oncol. 2016; 57:54-60. DOI: 10.1016/j.oraloncology.2016.04.005. View

16.

Xu W, Hiu T, Malarkannan S, Wang L . The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol. 2018; 15(5):438-446. PMC: 6068175. DOI: 10.1038/cmi.2017.148. View

17.

Blando J, Sharma A, Higa M, Zhao H, Vence L, Yadav S . Comparison of immune infiltrates in melanoma and pancreatic cancer highlights VISTA as a potential target in pancreatic cancer. Proc Natl Acad Sci U S A. 2019; 116(5):1692-1697. PMC: 6358697. DOI: 10.1073/pnas.1811067116. View

18.

Wang Q, Lou W, Di W, Wu X . Prognostic value of tumor PD-L1 expression combined with CD8 tumor infiltrating lymphocytes in high grade serous ovarian cancer. Int Immunopharmacol. 2017; 52:7-14. DOI: 10.1016/j.intimp.2017.08.017. View

19.

Zhang M, Pang H, Zhao W, Li Y, Yan L, Dong Z . VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma. BMC Cancer. 2018; 18(1):511. PMC: 5932869. DOI: 10.1186/s12885-018-4435-1. View

20.

ElTanbouly M, Schaafsma E, Noelle R, Lines J . VISTA: Coming of age as a multi-lineage immune checkpoint. Clin Exp Immunol. 2020; 200(2):120-130. PMC: 7160665. DOI: 10.1111/cei.13415. View