Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor
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
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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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 2

PDGFRA-mutant GIST is more immunologically active compared with KIT-mutant GIST.

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PDGFRA-mutant GIST is more immunologically active compared with KIT-mut...
(A) ESTIMATE and CYT scores (left) and CD45 and CD8 normalized counts (right) of all KIT- and PDGFRA-mutant GISTs (n = 61; Supplemental Table 3). (B). ESTIMATE and CYT scores (left) and CD45 and CD8 normalized counts (right) of UPG KIT- and PDGFRA-mutant GISTs (n = 22; Supplemental Table 4). (C) GSEA showing multiple immune pathways enriched in UPG PDGFRA-mutant compared with UPG KIT-mutant GISTs. NES, normalized enrichment score. (D) ×10 magnification CD45 and CD8 IHC staining in KIT- and PDGFRA-mutant GISTs. Red text indicates specimen was included in RNA-Seq cohort, while samples represented in black text were not included. Representative samples of n = 6 per group are shown. (E) CD45 (top) and CD8 (middle) quantification of IHC staining. n = 6 per group. The number of CD45+ and CD8+ cells per HPF was calculated by examining 5 HPFs per tumor and plotting the average per tumor. Bottom: CD45 expression by flow cytometry (for specimens in which flow cytometry data were available). *P < 0.05, t test. Bars indicate median.