Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor
Gerardo A. Vitiello, … , Shan Zeng, Ronald P. DeMatteo
Gerardo A. Vitiello, … , Shan Zeng, Ronald P. DeMatteo
Published February 14, 2019
Citation Information: J Clin Invest. 2019;129(5):1863-1877. https://doi.org/10.1172/JCI124108.
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Research Article Immunology Oncology

Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor

Abstract

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or PDGFRA gene. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising what we believe to be the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT- and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that in PDGFRA-mutant GISTs, immune cells were more numerous and had higher cytolytic activity than in KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokines, such as CXCL14, at a significantly higher level when compared with KIT-mutant GISTs and exhibited more diverse driver-derived neoepitope:HLA binding, both of which may contribute to PDGFRA-mutant GIST immunogenicity. Through machine learning, we generated gene expression–based immune profiles capable of differentiating KIT- and PDGFRA-mutant GISTs, and identified additional immune features of high–PD-1– and –PD-L1–expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.

Authors

Gerardo A. Vitiello, Timothy G. Bowler, Mengyuan Liu, Benjamin D. Medina, Jennifer Q. Zhang, Nesteene J. Param, Jennifer K. Loo, Rachel L. Goldfeder, Frederic Chibon, Ferdinand Rossi, Shan Zeng, Ronald P. DeMatteo

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Figure 4

PDGFRA- and KIT-mutant GISTs have distinct signaling and cytokine signatures.

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PDGFRA- and KIT-mutant GISTs have distinct signaling and cytokine signa...
GSEA showing enrichment of (A) PDGFRA signaling, PI3K signaling, and (B) cytokine signaling pathways in UPG PDGFRA- compared with UPG KIT-mutant GISTs (n = 22). (C) Distribution of cytokines between UPG KIT- and UPG PDGFRA-mutant GISTs, by RNA-Seq. Adjusted P < 0.05 as calculated by DESeq2. All data points are shown; boxes define the interquartile range, with whiskers extending to lowest and highest data points. (D) Left: Relative CXCL14 mRNA expression by qRT-PCR in KIT- (n = 7) and PDGFRA-mutant (n = 7) GISTs from the RNA-Seq cohort, compared with the GIST-T1 cell line (expression set at 1; data not shown). Right: CXCL14 mRNA expression relative to GAPDH × 106 in UPG KIT- and PDGFRA-mutant GISTs. Horizontal dotted line represents CXCL14 mRNA expression needed to induce tumor regression (31). *P < 0.05, t test. Bars indicate the median.