Expression of PD-L1, indoleamine 2,3-dioxygenase and the immune microenvironment in gastric adenocarcinoma

Abstract

Introduction

The tumor microenvironment is increasingly important in several tumors. We studied the relationship of key players of immune microenvironment with clinicopathological parameters in gastric adenocarcinomas.

Methods

Tissue microarrays were constructed from gastrectomy specimens, 2004-2013. Immunohistochemistry was performed for programmed death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), tryptophanyl-tRNA synthetase (WARS), guanylate-binding protein 5 (GBP5), tumor-infiltrating lymphocytes (TIL) expressing CD3/CD8/FoxP3/PD1, and mismatch repair proteins (MMRs) MLH1, PMS2, MSH2 and MSH6. Clinicopathological parameters and clinical follow-up were recorded.

Results

The study included 86 patients, median follow-up was 34 months (0-148). Tumor types were 45% tubular, 38% diffuse, 17% mixed. PD-L1 was positive in 70%, epithelial IDO in 58%, stromal IDO in 91%, epithelial WARS in 67%, stromal WARS in 100%, epithelial GBP5 in 53%, and stromal GBP5 in 71%. MMR-deficiency was found in 22%. There was no difference in biomarker expression by histological subtype, with exception fewer diffuse-type being MMR-deficient. Low stromal IDO was associated with decreased progression-free, overall and disease-specific survival. PD-L1-positive tumors were larger with MMR-deficiency and with increasing TILs, and had significantly higher FoxP3- TILs.

Conclusions

PD-L1 is expressed in a large proportion of gastric carcinomas suggesting that therapy targeting this pathway could be relevant to many patients. PD-L1 expression and MMR-deficiency are associated with increased TILs and larger tumor size, emphasizing their role in tumor biology. Higher stromal IDO expression is associated with better prognosis. Finally, we observed that immune modulators WARS and GBP5 are highly expressed in gastric adenocarcinomas, suggesting an important role in tumor pathobiology.

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