Identification of shared tumor epitopes from endogenous retroviruses inducing high-avidity cytotoxic T cells for cancer immunotherapy

Abstract

Human endogenous retroviruses (HERVs) represent 8% of the human genome. HERV products may represent tumor antigens relevant for cancer immunotherapy. We developed a bioinformatic approach to identify shared CD8 + T cell epitopes derived from cancer-associated HERVs in solid tumors. Six candidates among the most commonly shared HLA-A2 epitopes with evidence of translation were selected for immunological evaluation. In vitro priming assays confirmed the immunogenicity of these epitopes, which induced high-avidity CD8 + T cell clones. These T cells specifically recognize and kill HLA-A2 + tumor cells presenting HERV epitopes on HLA molecules, as demonstrated by mass spectrometry. Furthermore, epitope-specific CD8 + T cells were identified by dextramer staining among tumor-infiltrating lymphocytes from HLA-A2 + patients with breast cancer. Last, we showed that HERV-specific T cells lyse patient-derived organoids. These shared virus-like epitopes are of major interest for the development of cancer vaccines or T cell–based immunotherapies, especially in tumors with low/intermediate mutational burden.

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

“…We then examined whether the predicted HERV‐derived HLA‐A*02 epitopes could elicit an immune response in AML patients. We selected 8 different HLA‐A*02 epitopes among the top candidates in the additive model, focusing on peptides already identified as immunogenic in our lab (P1, P2, P4, and P6) or peptides preselected in a previous study in solid tumors but for which the immunogenicity has so far not been confirmed (P15, P16, P18, and P20) 55 . Bone marrow‐infiltrating lymphocytes (MILs) were expanded from bone marrow mononuclear cells (BMMCs) of HLA‐A*02 AML patients at diagnosis.…”

Spatiotemporal evolution of the ccRCC microenvironment links intra-tumoral heterogeneity to immune escape

“…A recent study [52] identified tumor infiltrating lymphocyte specific HERV epitopes that are translated, can bind to MHC I complex, and induce high-avidity cytotoxic T cells. In [52] as well as other previous reports [53], over expression of HERVs on tumor cells has been reported and a link to ICI response has been documented [54].…”

“…A recent study [52] identified tumor infiltrating lymphocyte specific HERV epitopes that are translated, can bind to MHC I complex, and induce high-avidity cytotoxic T cells. In [52] as well as other previous reports [53], over expression of HERVs on tumor cells has been reported and a link to ICI response has been documented [54]. To interrogate other tumor intrinsic features associated with immune response in our cohort we utilized our deep RNA sequencing (∼200 millions read/library) to quantify HERV expression.…”

“…Due to the limitations of HERV quantification using WTS, we could not rule out that a strong correlation between HERV and TIL abundance might be due to expression of HERV on immune cells. However, the expression of HERV on ccRCC tumor cells has been previously shown [59] and their immunogenicity is well-established [52]. Nevertheless, rigorous determination in future studies of cell-specific expression of HERVs will be critical to understanding their putative association with ICI response.…”

Influenza A Virus Infection Reactivates Human Endogenous Retroviruses Associated with Modulation of Antiviral Immunity

“…Moreover, HERV-derived proteins, such as the HERV-W envelope protein, have been reported to induce cytokine production via TLR signaling [ 16 , 17 ]. Several recent reports have shown that HERV-derived proteins can also stimulate the adaptive immune system by inducing a T or B-cell response [ 18 , 19 ]. Moreover, HERV-derived long non-coding RNAs (lncRNA) can have immunostimulatory functions [ 20 ], and HERV-derived promoters or enhancers can impact the expression of inflammatory genes, which influence antiviral immunity [ 2 , 6 , 21 ].…”