Identification of discrepancy between CTLA4 expression and CTLA4 activation in gastric cancer

Abstract

Objective: Recently, immune checkpoints blockers showed higher anti-tumor activity for advanced gastric cancer (GC). The purpose of the study is to find out predictive biomarkers related to anti-cytotoxic lymphocyte antigen 4 (CTLA4) therapy.

Materials and methods: Datasets of gene expression omnibus (GEO), the cancer genome atlas (TCGA), and gene set enrichment analysis (GESA) were extracted. Differential expression of CTLA4 between cancer tissues and normal mucosa, enrichment of WT (wild type) vs. CTLA4_KO (knockout) upregulated gene set and clinical significance were analyzed. The expression of CTLA4, CD3, and granzyme A (GZMA) were validated on 30 cases of Chinese GC. Microsatellite instability (MSI) marker MLH1 and Epstein-Barr virus (EBV) marker EBER were examined on 30 cases of Chinese GC by immunohistochemistry and in situ hybridization.

Results: CTLA4 was upregulated in GC tissue relative to normal mucosa in datasets of GSE27342 (fold change = 1.586, p < .001) and GSE63089 (fold change = 1.365, p < .001). Increased CTLA4 expression was positively related to CTLA4 activation. EBV-associated GC (EBVaGC) and microsatellite instability GC (MSIGC) disclosed higher CTLA4 levels than other GCs. Genomic stability GC (GSGC) also showed higher enrichment score of CTLA4 activation. CTLA4 activation resulted in shorter overall survival in GC. The expression level of CTLA4 was well correlated to expression levels of GZMA (R = 0.701, p < .001) and CD3 (R = 0.750, p < .001).

Conclusions: Based on bioinformatics analysis, GSGC should be worth noticed as a potential GC subtypes responsive to anti-CTLA4 treatment.

Keywords:

• Gastric cancer
• CTLA4
• molecular classification
• immunotherapy

Acknowledgments

We thank the NCBI for permission to use GEO (GSE27342, GSE63089, and GSE62254) and TCGA database.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the Scientific Research Foundation of Ningxia Medical University (No. XT2015021); the National Key R&D Program of China (2017YFC0908300 and 2016YFC1303200); the National Natural Science Foundation of China (81772505 and 81372644); Shanghai Science and Technology Committee (18411953100), the Cross-Institutes Research Fund of Shanghai Jiao Tong University (YG2017ZD01and YG2015MS62); Innovation Foundation of Translational Medicine of Shanghai Jiao Tong University School of Medicine (15ZH4001, TM201617, and TM201702); and Technology Transfer Project of Science & Technology Dept. Shanghai Jiao Tong University School of Medicine.