Bleomycin alters intratumoral immune response of EBV-associated gastric cancer by ENTPD8 and PCOLCE2

Abstract

Background EBV-associated gastric cancer (EBVaGC) with high PD-L1 level, is most likely to be the next subgroup benefited from immunotherapy. However, complicated with histological and aetiological heterogeneity, tolerance persists which was usually alleviated by clinical adjuvant chemotherapy (bleomycin). Identifying biomarkers of intratumoral immune response was critical for further understanding the direct mechanism of immunotherapy effectiveness. Method Firstly, to identify gene sets involved in both GC tumorigenesis and EBV infection, a transcriptome sequencing data (GSE51575) was collected for different expression gene (DEG) screening and functional enrichment analysis. Through constructing a prognostic model based on 25 repeated DEGs and evaluating immune correlations subsequently, the influence of ENTPD8 and PCOLCE2 in prognosis and immunotherapy was confirmed. In addition, the binding energy between bleomycin and targets was calculated based on hydrogen bond. Result A total of 572 down- and 162 up-regulated genes in normal tissue vs. GC tissue while 196 down- and 240 up-regulated genes in EBVnGC vs. EBVaGC were detected with logFC ≥ 2 and p-value ≤ 0.05. Among them, ENTPD8 and PCOLCE2 were reduced in EBVaGC which was associated with prognosis significantly and mediated dysregulation of immune response inversely. Besides, the expression trends of ENTPD8 (positive) and PCOLCE2 (negative) were also opposite when binding to bleomycin with the most stable binding energy-4.589 kcal/mol and − 4.025 kcal/mol, respectively. Conclusion Summarily, the improvement of immunotherapy caused by bleomycin as an adjuvant chemotherapy drug may mainly depend on the fluctuation of intratumoral immune response in EBVaGC mediated by the expression of ENTPD8 and PCOLCE2.