Abstract B129: Human endogenous retroviruses as a potential reservoir for T-cell mediated cancer immunotherapy

Abstract

Epigenetic modulation using DNA methyltransferase inhibitors (DNMTis), such as 5-azacytidine (5-aza-CR), have been shown to affect the cellular immunogenicity in vitro through upregulations of human endogenous retroviruses (HERV) leading to activation of the INFγ response pathway. HERVs comprise up to 8% of the human genome, and may hold a large reservoir of potential tumor antigens.We examined the in vivo efficacy of 5-aza-CR in terms of upregulations of HERV expression during standard treatment regimen, as well as the ability of such HERV transcripts to form T-cell antigens leading to measurable T-cell recognition upon treatment. We have studied 66 HERV genes that have been shown to be transcribed in human tissues. To identify HERV derived immune recognition, we generated a library of 1169 HERV derived potential antigenic peptides restricted to most abundant MHC class I molecules in the Caucasian population. Peripheral blood mononuclear cells (PBMCs) from a cohort of 19 patients and bone marrow samples from a cohort of 11 patients, treated with DNMTis for different hematological malignancies (MDS, AML, and CMML) were used to detect CD8+ T-cells reactive to ERV-derived peptides. We detected CD8+ T-cells specific to several HERV-derived peptides both in healthy and diseased individuals. Further, in an additional cohort of patients we examined expression level of these HERVs by RNA seq analysis and compared with healthy individuals demonstrating a disease associated upregulation of HERVs in hematological malignancies. Presence of T-cells reactive to HERV antigens and enhanced expression of HERVs in these malignancies suggest that HERVs may indeed provide a pool of shared tumor associated antigens. These antigens could potentially be enhanced through DNMTi treatment and may provide a target for T-cell mediated immunotherapy. Citation Format: Sunil Kumar Saini, Anne-Mette Bjerregaard, Andreas D. Orskov, Ashwin Unnikrishnan, Staffan Holmberg, Govardhan Anande, Amalie Kai Bentzen, Zoltan Szallasi, Aron C. Eklund, Kirsten Gronbaek, Sine Reker Hadrup. Human endogenous retroviruses as a potential reservoir for T-cell mediated cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B129.