Role of Immune Microenvironment in Gastrointestinal Stromal Tumors

Abstract

Introduction

The immune microenvironment is a prognostic factor for various malignancies. The significance of key players of this immune microenvironment including tumor-infiltrating lymphocytes and expression of programmed death-ligand 1 (PD-L1), indoleamine-2,3-dioxygenase (IDO), and tryptophanyl-tRNA synthetase (WARS) in gastrointestinal stromal tumors (GISTs) is largely unknown.

Methods

Tissue microarrays were constructed from pathology files, 1996-2016. Immunohistochemistry for PD-L1, IDO, WARS was correlated with tumor size, mitoses, and outcomes. Tumor infiltrating lymphocytes (TILs) expressing CD3, CD4, CD8, FoxP3, and GBP5 were counted.

Results

129 GISTs were analyzed. Mean patient age was 62.5 years; 52.0% were male. Tumor location included 89 stomach (69.0%), 33 small bowel (25.6%), 7 other (5.4%). Mean tumor size was 5.6 cm; mean mitoses were 7.2/50HPF. Nineteen patients (15.0%) developed disease progression, to abdominal wall (n=8), liver (n=6), and elsewhere (n=5). Median progression-free survival was 56.6 months; 5 patients died of disease. PD-L1 was positive in 87/126 tumor samples (69.0%), 114/127 tumors were IDO-positive (89.8%), and 60/127 were positive for WARS (47.2%). PD-L1 was associated with increased size (p=0.01), necrosis (p=0.018), and mitoses (p=0.006). Disease progression was not associated with PD-L1 (p=0.44), IDO (p=0.14), or WARS (p=0.36) expression. PD-L1-positive GISTs with CD8- or CD3-positive TILs were significantly smaller than tumors with CD8- or CD3-negative TILs.

Conclusions

PD-L1 expression was associated with increased size and mitoses. High CD8- or CD3-positive TIL counts were associated with decreased PD-L1/IDO-positive GIST size. PD-L1 and IDO could be significant in GIST tumor biology and invite consideration of immunotherapy as a potential treatment option.

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