THU494 VHL Protein Deficiency Alters The Immune Microenvironment Of Pancreatic Neuroendocrine Neoplasms

Abstract

Abstract Disclosure: A. Chmelnik: None. A. Telerman: None. A. Tirosh: None. Introduction - Pancreatic neuroendocrine tumors (PanNENs) may develop sporadically or as part of an inherited disease, such as von Hippel-Lindau (VHL). VHL disease is caused by a germline pathogenic variant in the VHL gene encoding VHL protein (pVHL). Hypoxia inducible factor (HIF) is responsible for cellular oxygen supply. Its degradation is mediated by pVHL via ubiquitination in normoxic states. In pVHL-deficient state leads to HIF overexpression and pseudohypoxia. Several studies suggested immunomodulatory role for HIF in kidney cancer. Aims- To assess the impact of pseudohypoxia on PanNEN immune tumor microenvironment (iTME). Methods- A total of 16 vPanNEN and 23 sPanNEN were processed. Whole genome DNA methylation was performed by Illumine Infinium EPIC Array and analyzed using ChAMP on RStudio. Immune cells composition was compared using methylation-based deconvolution algorithms (MethylResolver, Robust Partial Correlations, Constrained Projection and Cibersort), and gene set enrichment analysis identified pathways affected in each group based on promoter methylation analysis. Results- Unsupervised hierarchical analysis of immune-related gene promoter methylation demonstrated separation of vPanNEN vs. sPanNEN. In GSEA analysis methylation was altered in immune memory-related genes in vPanNEN, and in T cells receptors-related genes in sPanNEN. Deconvolution algorithms revealed a lower fraction of CD4 and NK cells (p<0.05) and a lower PD-L1 expression in vPanNENs (p=0.037). Conclusion- Pseudohypoxic vPanNEN have distinct iTME than sPanNEN, in immune cells composition and PD-L1 expression. Presentation: Thursday, June 15, 2023