Journal
IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY
Volume 41, Issue 3, Pages 386-393Publisher
TAYLOR & FRANCIS LTD
DOI: 10.1080/08923973.2018.1533968
Keywords
Gastric cancer; CTLA4; molecular classification; immunotherapy
Categories
Funding
- Scientific Research Foundation of Ningxia Medical University [XT2015021]
- National Key R&D Program of China [2017YFC0908300, 2016YFC1303200]
- National Natural Science Foundation of China [81772505, 81372644]
- Shanghai Science and Technology Committee [18411953100]
- CrossInstitutes Research Fund of Shanghai Jiao Tong University [YG2017ZD01, YG2015MS62]
- Innovation Foundation of Translational Medicine of Shanghai Jiao Tong University School of Medicine [15ZH4001, TM201617, TM201702]
- Technology Transfer Project of Science & Technology Dept. Shanghai Jiao Tong University School of Medicine
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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.
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