Gastrointestinal stromal tumors (GIST) are the most frequently occurring digestive sarcomas. The prognosis of localized GIST is heterogeneous, notably for patients with an Armed Forces Institute of Pathology (AFIP) intermediate or high risk of relapse. Despite imatinib effectiveness, it is crucial to develop therapies able to overcome the resistance mechanisms. The immune system represents an attractive prognostic and therapeutic target. The Programmed cell Death 1 (PD1)/programmed cell death ligand 1 (PDL1) pathway is a key inhibitor of the immune response; recently, anti-PD1 and anti-PDL1 drugs showed very promising results in patients with solid tumors. However, PDL1 expression has never been studied in GIST. Our objective was to analyze PDL1 expression in a large series of clinical samples. We analyzed mRNA expression data of 139 operated imatinib-untreated localized GIST profiled using DNA microarrays and searched for correlations with histoclinical features including postoperative metastatic relapse. PDL1 expression was heterogeneous across tumors and was higher in AFIP low-risk than in high-risk samples, and in samples without than with metastatic relapse. PDL1 expression was associated with immunity-related parameters such as T-cell-specific and CD8+ T-cell-specific gene expression signatures and probabilities of activation of interferon α (IFNα), IFNγ, and tumor necrosis factor α (TNFα) pathways, suggesting positive correlation with a cytotoxic T-cell response. In multivariate analysis, the PDL1-low group was associated with a higher metastatic risk independently of the AFIP classification and the KIT mutational status. In conclusion, PDL1 expression refines the prediction of metastatic relapse in localized GIST and might improve our ability to better tailor adjuvant imatinib. In the metastatic setting, PDL1 expression might guide the use of PDL1 inhibitors, alone or associated with tyrosine kinase inhibitors.
Keywords: AFIP, Armed Forces Institute of Pathology; DNA microarray; FDR, false discovery rate; GEO, gene expression omnibus; GES, gene expression signatures; GIST; GIST, gastrointestinal stromal tumors; GO, gene ontology; IHC, immunohistochemistry; ISH, in situ hybridization; MFS, metastasis-free survival; MHC, major histocompatibility complex; NCBI, National Center for Biotechnology Information; NK cells, natural killer cells; PCA, principal component analysis; PD1, programmed cell death 1; PDGFRA, platelet-derived growth factor receptor α; PDL1; PDL1, programmed cell death ligand 1; REMARK, REcommendations for tumor MARKer; RMA, robust multichip average; ROC, receiver operating characteristic; TILs, tumor-infiltrating lymphocytes; Treg, regulatory T cells; WT, wild type; gene expression; immune response; prognosis; qRT-PCR, quantitative reverse transcription-polymerase chain reaction.