ERVs are consistently expressed and immunogenic in GBM, representing a scalable, tumor-specific antigen source that may overcome limitations of low mutational burden and provide a proof-of-concept for personalized vaccines targeting ERV-derived neoantigens.
Abstract
Glioblastoma (GBM) remains refractory to immunotherapy due to low mutational burden and limited neoantigens. Aberrant expression of endogenous retroviral elements (ERVs), reactivated insertions of ancient viruses within the genome, may provide a source of tumor-specific antigens for personalized vaccines targeting traditional and ERV-derived neoantigens.
Tumor and matched normal tissues from 25 GBM patients, including 18 long-term survivors (LTS; >5 years) and 7 short-term survivors (STS; 12—18 months), underwent whole-genome and RNA sequencing. Candidate antigens were predicted using two AI-based pipelines: one for mutation-derived neoantigens and one for ERV-derived antigens. Predicted epitopes were ranked by expression, MHC class I and II binding affinity, clonality, and immunogenicity. Top candidates informed the design of a personalized DNA vaccine encoding 10 patient-specific neoantigen sequences with a CCL19 adjuvant to enhance dendritic cell recruitment.
High-quality canonical neoantigens were rare (median 3/ patient), consistent with prior reports. Yet, all tumors expressed abundant, patient-specific ERV transcripts independent of mutation load. ERV-derived epitopes exhibited strong predicted MHC class I and II binding, comparable to viral antigens, with 22 of 25 tumors containing ERV peptides suitable for vaccine inclusion. These mapped primarily to HERV-K and HERV-W families and frequently overlapped interferon-stimulated loci. Comparison of LTS and STS cohorts is ongoing to define ERV expression patterns associated with durable immune control.
ERVs are consistently expressed and immunogenic in GBM, representing a scalable, tumor-specific antigen source that may overcome limitations of low mutational burden. These data provide a proof-of-concept for personalized vaccines targeting ERV-derived neoantigens.
Duke Brain Tumor Omics Program Fellow
Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)
This review outlines the molecular mechanisms driving neoantigen generation in CRC, including frameshift mutations, single-nucleotide variants, alternative RNA splicing, and circular RNA-derived epitopes, and evaluates neoantigen-directed therapeutic platforms, encompassing personalized neoantigen vaccines and adoptive T-cell therapies that are engineered to recognize neoantigen-derived epitopes.
Na Wang, Yi-Meng Xia, Ping Wang et al.· Medical Oncology· 0 citations
T cells mediate anti-cancer immune responses through recognition of neoantigens - cancer-specific, mutation-derived peptides presented by MHC proteins. “Public” neoantigens are a subset of neoantigens derived from recurrently mutated driver genes and presented by common HLA alleles, making them ideal immunotherapy targets. NRAS is the second most frequently mutated RAS isoform, and its common hotspot mutations (Q61R, Q61K, and Q61L) give rise to a family of HLA-A*01:01 (A1)-restricted public neoantigens.
This study aims to elucidate how the NRAS Q61 neoantigens are structurally and biophysically distinct from their wild-type (WT) counterpart and to resolve the mechanisms that enable a panel of patient-derived TCRs to achieve neoantigen specificity.
Differential scanning fluorimetry shows that each neoantigen and the WT peptide bind A1 with comparable affinity. X-ray crystal structures of the neoantigen/A1 and WT/A1 complexes reveal that the p7Q side chain of the WT peptide is “tethered” to the α2 helix of A1 via a network of hydrogen bonds. This network is disrupted with all neoantigens, increasing the solvent accessibility of the mutated p7 side chains and facilitating potential TCR interactions. In surface plasmon resonance (SPR) binding experiments, one TCR (TCR11L) binds all three neoantigens (Q61R, Q61K, Q61L) and the WT peptide with high affinity. Crystal structures reveal that TCR11L primarily contacts the penultimate p9E of the peptides, bypassing the p7 mutation site. However, T cell-based functional assays show that TCR11L responds only to the Q61K and Q61L neoantigens. Intriguingly, SPR kinetic analyses reveal significantly slower dissociation rates for TCR11L complexed with Q61K and Q61L compared to Q61R and WT, suggesting that the functional specificity of TCR11L is kinetically driven.
Collectively, these biophysical, structural, and functional studies reveal how TCR promiscuity can be exploited to enhance scalability in neoantigen-targeting therapies.
NIH R01CA286507
Vaccines and Immunotherapy (VAC)
Gihan Perera, Iñaki Etxeberria, Christopher A. Klebanoff et al.· Journal of Immunology· 0 citations
Background Mutation-derived neoantigens, typically identified in primary tumors, are emerging therapeutic targets for personalized cancer vaccines and adoptive T-cell therapies. However, clinical efficacy of neoantigen-directed therapies in patients with metastatic disease remains limited, partly due to inter-site genetic heterogeneity. We investigated whether ubiquitous neoantigens–derived from mutations shared across all tumor sites–could provide more effective, durable targets, particularly in patients undergoing resection of metastatic lesions. Methods Whole-exome and RNA sequencing were performed on 14 tumor samples (primary and 13 synchronous nodal metastases) from a treatment-naïve patient with pancreatic neuroendocrine tumor (PNET). Ubiquitous mutations were identified bioinformatically, and their immunogenicity assessed using in-vitro stimulation of autologous peripheral blood mononuclear cells followed by IFN-γ ELISpot assay. Neoantigen-specific T-cell clonotypes were further identified by HLA-tetramer staining and single-cell RNA/TCR sequencing. Neoantigen-reactive clonotypes identified in peripheral blood were tracked across multiple metastatic sites using bulk TCRβ repertoire sequencing. Results Among 1,195 non-synonymous mutations detected, eight were shared across all 14 tumor sites. Of these, one encoded a neoantigen that elicited a reproducible IFN-γ ELISpot response in peripheral blood, confirming its immunogenicity. Further, we identified the corresponding neoantigen-reactive TCR clonotypes in blood. Comparison with bulk TCRβ repertoires from eight metastatic sites showed that these clonotypes were present in every site analyzed, with evidence of local clonal expansion. Conclusion This study provides direct evidence that a single ubiquitous mutation-derived neoantigen can generate systemic T-cell responses and clonotype expansion across multiple metastatic sites in a TMB-low, TIL-low tumor. Our findings support incorporating mutation-sharing status across metastases as a key criterion for neoantigen selection in cancer vaccines and adoptive T-cell therapies. This approach could inform the design of neoantigen-directed immunotherapies in metastatic PNET and potentially other metastatic solid tumors. What is already known on this topic Neoantigen-directed therapies, such as personalized cancer vaccines or adoptive T-cell transfer, can induce anti-tumor responses but have shown limited success in metastatic disease. One major barrier is genetic heterogeneity between tumor sites, suggesting that targeting ubiquitous mutations–those shared across all tumor sites–may improve the efficacy of such therapies. What this study adds In one patient with metastatic pancreatic neuroendocrine tumor involving 13 lymph nodes, we identified eight ubiquitous mutations, one of which generated a detectable neoantigen-specific T-cell response in blood. The corresponding T-cell clonotypes were found across all metastatic sites analyzed and showed evidence of clonal expansion, providing direct evidence of systemic and local recognition of a shared neoantigen in a TMB-low/TIL-low cancer. How this study might affect research, practice or policy These findings support incorporating mutation sharing across metastases as a key criterion in neoantigen selection for cancer vaccines and adoptive T-cell therapies. This strategy could enhance the relevance and durability of neoantigen- directed approaches in patients with metastatic disease.
J. Tanis, Katy J. McCann, F. E. Castañeda-Castro et al.· bioRxiv· 0 citations
The strongest current signal supports use in adjuvant, perioperative, and minimal residual disease settings, usually in combination with checkpoint blockade or other immune-modifying strategies, usually in combination with checkpoint blockade or other immune-modifying strategies.
Minglu Ge, Ning Wu· Cancer Treatment and Researc...· 0 citations
Endogenous retroviruses (ERVs) are remnants of germline retroviral infections that occurred over evolution and make up 5—8% of the human genome. Although ERVs are typically epigenetically silenced in healthy adult tissues, they are overexpressed in carcinomas and may represent a novel pool of immunotherapeutic targets. This study characterizes the ERV envelope protein ERVMER34-1 as a therapeutic target in cancer.
The expression of ERVMER34-1 in healthy adult and cancer tissues was assessed by IHC. Its immunogenicity in human PBMCs was evaluated by ELISPOT assays, and the lytic ability of specific T cells was assessed by live-cell imaging assays. In addition, a rationally designed ERVMER34-1—targeted therapeutic vaccine was tested for its ability to induce tumor clearance in two murine carcinoma models, as monotherapy or in combination with immuno-oncology agents.
The ERVMER34-1 protein is overexpressed in several human carcinomas while being absent in most healthy adult tissues. ERVMER34-1—specific T cells were detected in PBMCs of cancer patients but not healthy donors after overnight stimulation, yet reactive T cells expand readily from both groups after 7 days of in-vitro stimulation. These T cells selectively kill human carcinoma cell lines expressing ERVMER34-1. A rationally designed therapeutic vaccine targeting ERVMER34-1 mediated tumor control in two syngeneic murine tumors. When combined with checkpoint blockade, the vaccine induced tumor regression and promoted the expansion of neoepitope-reactive T cells, whose function was further enhanced by an FDA-approved IL-15 superagonist. The strong neoepitope response associates with an inflamed tumor microenvironment marked by increased CD8+ T-cell infiltration and improved tumor control.
This study supports the clinical development of a therapeutic cancer vaccine targeting the retroviral envelope protein ERVMER34-1, which would represent a new class of therapeutic cancer vaccine targeting ERVs.
This study was supported by the Intramural Research Program of the Center for Cancer Research, NCI, NIH
Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)
D. Hamilton, Maria del Mar Maldonado, Renee N. Donahue et al.· Journal of Immunology· 0 citations
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