Abstract 938: HHV-7-mediated downregulation of HLA-F: a mechanism for immune evasion in angiosarcoma

Abstract Background: Human herpesvirus-7 (HHV-7) is a ubiquitous, CD4+ T cell lymphotropic virus. It establishes lifelong latency and may reactivate, particularly in immunocompromised individuals. We had previously detected the presence of HHV-7 in two-thirds of angiosarcoma clinical samples. HHV-7-positive (HHV-7+) tumors were shown to be relatively enriched for B- and mast cells and had high tumor inflammation signature scores compared to HHV-7-negative tumors. Objective: To investigate HHV-7 pathogenesis in host cells and its role in angiosarcoma. Methods: A SupT1 infection model was established. Images and cell pellets were collected at Days 0 and 4 (early infection phase) and Days 8 and 14 (late infection phase) for bulk RNA-seq analysis. Gene expression data was validated with quantitative PCR (qPCR). RNA-seq and Nanostring gene expression profiling with the Pancancer IO360 panel were previously performed on HHV7+ fresh frozen and FFPE angiosarcoma samples respectively. Results: Infected SupT1 cells exhibited cytopathic effects (CPEs) such as membrane blebbing, syncytia formation and growth arrest during early infection phase. Cell lysis, followed by recovery of cell growth, were observed during late infection phase. RNA-seq revealed significant pathway alterations across the infection course, supporting these observations. Early infection showed notable upregulation in arachidonic acid metabolism and antigen processing and presentation pathways, indicating an anti-viral response in host cells. The downregulation in actin cytoskeleton and cell cycle pathways were seen, corresponding to the observed CPEs. During late infection, there was a significant downregulation in antigen processing and presentation pathways (padj. <0.05), suggesting immune evasion the virus, along with a significant downregulation of tumor suppressor genes such as RNF43 and CBFA2T3. Through the course of infection, a general upward trend of oncogenic and inflammatory pathways was seen, with the latter being observed in HHV-7+ angiosarcomas as well. Narrowing down on specific genes, we observed the significant downregulation of HLA-F and upregulation of HK2 in both late-stage SupT1 infection and HHV-7+ angiosarcomas, implicating these genes in immune evasion and tumor progression. Conclusions: Our study provides the first RNA-seq profiling of HHV-7 infection in host cells. The study reveals alterations in key cellular pathways that promote an immunosuppressive and pro-inflammatory environment. These changes likely facilitate tumor progression and immune evasion in angiosarcoma. Citation Format: Kuo-Chu Lai. Metabolic alterations in skeletal muscle and serum of tumor-bearing cachectic mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 286.