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Clin Cancer Res. 2018 Apr 1;24(7):1562-1573. doi: 10.1158/1078-0432.CCR-17-2542. Epub 2017 Dec 4.

Spatially Resolved and Quantitative Analysis of VISTA/PD-1H as a Novel Immunotherapy Target in Human Non-Small Cell Lung Cancer.

Author information

1
Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
2
Department of Public Health, Yale School of Medicine, New Haven, Connecticut.
3
Immunobiology, Yale School of Medicine, New Haven, Connecticut.
4
Solid Tumor Oncology, Cleveland Clinic Foundation, Cleveland, Ohio.
5
Oncology Unit GPP, Athens School of Medicine, Greece.
6
Medical Oncology and Yale Cancer Center, New Haven, Connecticut.
7
Department of Pathology, Yale School of Medicine, New Haven, Connecticut. kurt.schalper@yale.edu.

Abstract

Purpose: Determine the localized expression pattern and clinical significance of VISTA/PD-1H in human non-small cell lung cancer (NSCLC).Experimental Design: Using multiplex quantitative immunofluorescence (QIF), we performed localized measurements of VISTA, PD-1, and PD-L1 protein in 758 stage I-IV NSCLCs from 3 independent cohorts represented in tissue microarray format. The targets were selectively measured in cytokeratin+ tumor epithelial cells, CD3+ T cells, CD4+ T-helper cells, CD8+ cytotoxic T cells, CD20+ B lymphocytes and CD68+ tumor-associated macrophages. We determined the association between the targets, clinicopathological/molecular variables and survival. Genomic analyses of lung cancer cases from TCGA were also performed.Results: VISTA protein was detected in 99% of NSCLCs with a predominant membranous/cytoplasmic staining pattern. Expression in tumor and stromal cells was seen in 21% and 98% of cases, respectively. The levels of VISTA were positively associated with PD-L1, PD-1, CD8+ T cells and CD68+ macrophages. VISTA expression was higher in T-lymphocytes than in macrophages; and in cytotoxic T cells than in T-helper cells. Elevated VISTA was associated with absence of EGFR mutations and lower mutational burden in lung adenocarcinomas. Presence of VISTA in tumor compartment predicted longer 5-year survival.Conclusions: VISTA is frequently expressed in human NSCLC and shows association with increased tumor-infiltrating lymphocytes, PD-1 axis markers, specific genomic alterations and outcome. These results support the immunomodulatory role of VISTA in human NSCLC and suggests its potential as therapeutic target. Clin Cancer Res; 24(7); 1562-73. ©2017 AACR.

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