HERVs characterize normal and leukemia stem cells and represent a source of shared epitopes for cancer immunotherapy

Abstract

Human endogenous retroviruses (HERVs) represent 8% of the human genome. The expression of HERVs and their immune impact have not been extensively studied in Acute Myeloid Leukemia (AML). In this study, we used a reference of 14 968 HERV functional units to provide a thorough analysis of HERV expression in normal and AML bone marrow cells. We show that the HERV retrotranscriptome accurately characterizes normal and leukemic cell subpopulations, including leukemia stem cells, in line with different epigenetic profiles. We then show that HERV expression delineates AML subtypes with different prognoses. We finally propose a method to select and prioritize CD8+ T cell epitopes derived from AML‐specific HERVs and we show that lymphocytes infiltrating patient bone marrow at diagnosis contain naturally occurring CD8+ T cells against these HERV epitopes. We also provide in vitro data supporting the functionality of HERV‐specific CD8+ T‐cells against AML cells. These results show that HERVs represent an important source of genetic information that can help enhancing disease stratification or biomarker identification and an important reservoir of alternative tumor‐specific T cell epitopes relevant for cancer immunotherapy.

Targeting Heterochromatin Eliminates Malignant Hematopoietic Stem and Progenitor Cells in Chronic Myelomonocytic Leukemia Through Reactivation of Retroelements and Innate Immune pathways

“…Focusing on ERVs that displayed the most significant differential expression upon DAC/UNC0638 treatment, we conducted a loci-based quantification, as described in our previous work (31), incorporating four additional patient samples. We identified 2,120 differentially expressed ERV loci (p<0.05, FC 1.5) between untreated and DAC/UNC0638 conditions, including 2,056 (97%) upregulated and 64 (3%) downregulated loci (Fig.…”

“…Libraries were pooled and sequenced in (2 x 100bp) on the NovaSeq-6000 (Illumina). Gene and ERV expression was quantified as described (11,31) (supplementary methods).…”

A Systems Biology Approach on the Regulatory Footprint of Human Endogenous Retroviruses (HERVs)

“…The probable involvement of HERVs in cancer is a long-enduring concept [ 68 , 99 , 100 ]. Specifically, HERV transcripts have been found upregulated in prostate [ 101 ], kidney [ 102 ] breast [ 102 , 103 , 104 , 105 ], hepatocellular [ 106 ], ovarian [ 107 ] and colorectal cancer [ 108 , 109 ], as well as in soft tissue sarcoma [ 110 ] and leukemia [ 111 ]. Recent data suggest a connection between HERVs and cancer stemness [ 112 ].…”

“…Recent data suggest a connection between HERVs and cancer stemness [ 112 ]. In particular, HERV retrotranscriptome has been found to accurately characterize leukemia stem cells [ 111 ] and to show a widespread expression that may be tissue- and developmental-stage specific [ 113 ]. The aforementioned data agree with the notion that HERV retrotranscriptome can characterize normal and cancer cells, while the question remains whether thay act as the main regulatory elements in such condition or as passive transcribed elements.…”

Epitope screening and vaccine molecule design of PRRSV GP3 and GP5 protein based on immunoinformatics

“…In order to increase the prediction accuracy, two servers, NetMHCpan EL4.1 (http://tools.iedb.org/mhci/; Access: 2023.01) and NetMHCpan4.1 (https://services.healthtech.dtu.dk/service.php%3F NetMHCpan‐4.1; Access: 2023.01) were used for comprehensive judgement of CTL candidate epitope prediction 26,27 . Among them, NetMHCpan EL4.1 was based on the consensus recommendation method, and NetMHCpan4.1 was based on the artificial neural network algorithm, which evaluates the binding ability of each peptide to a specific MHC⁃class I molecule and the epitope prediction score.…”