Immune Infiltration, Cancer Stemness, and Targeted Therapy in Gastrointestinal Stromal Tumor.

Jingjing Wang,Minquan Lin,Changhua Zhang,Mingzhe Li,Wenhui Wu,Hui Ren,Jingyao Chen,Qianlin Zeng,Juanjuan Han,Yulong He

doi:10.3389/fimmu.2021.691713

Abstract

ObjectiveTo investigate the characteristics of the tumor immune microenvironment in patients with gastrointestinal stromal tumor (GIST) and identify cancer stem-like properties of GIST to screen potential druggable molecular targets.MethodsThe gene expression data of 60 patients with GIST was retrieved from the Array Express database. CIBERSORT was applied to calculate the level of immune infiltration. ssGSEA and ESTIMATE were used to calculate the cancer stemness index and tissue purity. The Connectivity Map (CMAP) database was implemented to screen targeted drugs based on cancer stem-like properties of GIST.ResultThere was a difference in the level of immune infiltration between the metastasis and non-metastasis GIST groups. The low level of T-cell infiltration was correlated with high tumor purity and tumor stemness index, and the correlation coefficients were -0.87 and -0.61 (p < 0.001), respectively. Furthermore, there was a positive correlation between cancer stemness index and cell purity (p < 0.001). The cancer stemness index in the metastasis group was higher than that in the non-metastasis group (p = 0.0017). After adjusting for tumor purity, there was no significant correlation between T-cell infiltration and cancer stemness index (p = 0.086). Through the pharmacological mechanism of topoisomerase inhibitors, six molecular complexes may be the targets of GIST treatment.ConclusionImmune infiltration in GIST patients is related to cancer stem-like properties, and the correlation relies on tumor purity. Cancer stemness index can be used as a new predictive biomarker of tumor metastasis and targets of drug therapy for GIST patients.

Highlights

Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal mesenchymal tumor
We downloaded the gene expression chip data and clinical information of 60 GIST patients from the Array Express database, which consisted of 15 metastatic patients and 45 non-metastatic patients
In order to investigate the immune infiltration of GIST, the CIBERSORT algorithm was employed to calculate the expression profiles of 22 kinds of immune cells

Summary

Introduction

Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal mesenchymal tumor. The common sites of GIST are the stomach, intestine, colon, etc. It originates from interstitial cells of Cajal (ICC) or more primitive progenitor cells [1]. There are functional mutations in GIST due to acquisition of c-kit gene (75%–80%) or PDGFRA gene (5%–10%) [2,3,4,5,6]. These mutations can lead to the continuous activation of ligandindependent receptor proteins, and downstream signal transduction pathways being activated, and afterward cell apoptosis being inhibited and cell proliferation being promoted, which is considered to be the classic pathogenesis of GIST. It was reported that all GIST patients represented malignant behavior, with features of invasion, and metastasis

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