Engineering human endogenous retrovirus-K for improving immunogenicity and broad cancer targeting
8 affiliations
- 1Department of Immunology and Microbiology, University of Copenhagen
- 2HERVolution Therapeutics ApS
- 3Department of Biomedical Sciences, University of Copenhagen
- 4Department of Veterinary Biomedical Sciences, School of Veterinary Medicines and Biomedical Sciences, IPB University
- 5Primate Research Center, IPB University
- 6Revvity Gene Delivery GmbH
- 7Department of Clinical Medicine, University of Copenhagen
- 8Department of Genomic Medicine, Copenhagen University Hospital
Abstract
Background HERV-K (HML-2) is the most studied transcriptionally active endogenous retrovirus in human cancers, yet immune tolerance and incomplete mechanistic understanding have impeded its clinical use as an immunotherapy target. We hypothesized that rational engineering of the HERV-K envelope putative immunosuppressive domain (ISD) could improve immunogenicity. Methods We performed a mutational screen across the ISD region, evaluated NF-κB activation and then analyzed antigen expression in human monocyte-derived dendritic cells (moDCs) using flow cytometry, RNA-seq, and TEM. Human PBMCs were expanded with HERV-K–transduced moDCs to assess T cell priming and expansion ex vivo. Immunogenicity was tested in mice, HERV-K transgenic mice, and cynomolgus macaques using adenoviral and LNP-mRNA vectors. Antitumor efficacy was evaluated in a murine metastatic renal carcinoma HERV-K expressing tumor model. Results Engineering the HERV-K envelope ISD to Q525A (ISDmut) enhanced NF-κB activation, antigen expression, and antigen presentation and cell death associated gene expression pathways in human dendritic cells while preserving virus-like particle assembly. HERV-K-ISDmut-transduced human dendritic cells expanded CD4+ and CD8+ T cells capable of recognizing HLA-matched, HERV-K expressing tumors, demonstrating that T cells from the human repertoire can be expanded ex vivo. In vivo, mRNA and adenoviral vectors encoding HERV-K-ISDmut elicited strong immune responses in mice, broke tolerance in HERV-K transgenic mice, and induced humoral responses in cynomolgus macaques. In mice, an adenovirus vectored HERV-K-ISDmut immunization further conferred increased survival in a murine renal carcinoma HERV-K expressing tumor model and benefitted from anti-PD-1 therapy. Conclusions These results show that the rational redesign of the HERV-K ISD generates a potent immunogen capable of expanding human T cells and mediating mechanistically relevant anti-tumor immunity. We propose that HERV-K-ISDmut antigens represent a promising platform for cancer immunotherapy which should be explored in future clinical trials.
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BibTeX
@article{muller2026engineering,
title = {{Engineering human endogenous retrovirus-K for improving immunogenicity and broad cancer targeting}},
author = {Mikkel Dons Müller and Lasse Neukirch and Emeline Ragonnaud and Amaia Vergara Bermejo and Joana Daradoumis and Victoria Jaded and Emilie Sofie Engdal and Felix Faas and Maria Perez-Penco and Cristina Picon-Jara and Karen Nørgaard Nielsen and Lara Duvnjak and Ditte Rahbaek Boilesen and Sara Kusiński and Isabella Skandorff and Nanna Skeltved and Lene Linh Ngoc Trinh and Louise Turner and Kaare Villum Grunddal and Huda Salahudin Darusman and Silmi Mariya and Silke Schrödel and Kristoffer Staal Rohrberg and Frederik Otzen Bagger and Christian Thirion and Per Thor Straten and Anne-Marie Carola Andersson and Peter Johannes Holst},
journal = {Journal of Translational Medicine},
year = {2026},
month = sep,
doi = {10.1186/s12967-026-09012-1},
url = {https://doi.org/10.1186/s12967-026-09012-1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Engineering human endogenous retrovirus-K for improving immunogenicity and broad cancer targeting
AU - Mikkel Dons Müller
AU - Lasse Neukirch
AU - Emeline Ragonnaud
AU - Amaia Vergara Bermejo
AU - Joana Daradoumis
AU - Victoria Jaded
AU - Emilie Sofie Engdal
AU - Felix Faas
AU - Maria Perez-Penco
AU - Cristina Picon-Jara
AU - Karen Nørgaard Nielsen
AU - Lara Duvnjak
AU - Ditte Rahbaek Boilesen
AU - Sara Kusiński
AU - Isabella Skandorff
AU - Nanna Skeltved
AU - Lene Linh Ngoc Trinh
AU - Louise Turner
AU - Kaare Villum Grunddal
AU - Huda Salahudin Darusman
AU - Silmi Mariya
AU - Silke Schrödel
AU - Kristoffer Staal Rohrberg
AU - Frederik Otzen Bagger
AU - Christian Thirion
AU - Per Thor Straten
AU - Anne-Marie Carola Andersson
AU - Peter Johannes Holst
PY - 2026
DA - 2026/09/01
JO - Journal of Translational Medicine
DO - 10.1186/s12967-026-09012-1
UR - https://doi.org/10.1186/s12967-026-09012-1
AB - Background HERV-K (HML-2) is the most studied transcriptionally active endogenous retrovirus in human cancers, yet immune tolerance and incomplete mechanistic understanding have impeded its clinical use as an immunotherapy target. We hypothesized that rational engineering of the HERV-K envelope putative immunosuppressive domain (ISD) could improve immunogenicity. Methods We performed a mutational screen across the ISD region, evaluated NF-κB activation and then analyzed antigen expression in human monocyte-derived dendritic cells (moDCs) using flow cytometry, RNA-seq, and TEM. Human PBMCs were expanded with HERV-K–transduced moDCs to assess T cell priming and expansion ex vivo. Immunogenicity was tested in mice, HERV-K transgenic mice, and cynomolgus macaques using adenoviral and LNP-mRNA vectors. Antitumor efficacy was evaluated in a murine metastatic renal carcinoma HERV-K expressing tumor model. Results Engineering the HERV-K envelope ISD to Q525A (ISDmut) enhanced NF-κB activation, antigen expression, and antigen presentation and cell death associated gene expression pathways in human dendritic cells while preserving virus-like particle assembly. HERV-K-ISDmut-transduced human dendritic cells expanded CD4+ and CD8+ T cells capable of recognizing HLA-matched, HERV-K expressing tumors, demonstrating that T cells from the human repertoire can be expanded ex vivo. In vivo, mRNA and adenoviral vectors encoding HERV-K-ISDmut elicited strong immune responses in mice, broke tolerance in HERV-K transgenic mice, and induced humoral responses in cynomolgus macaques. In mice, an adenovirus vectored HERV-K-ISDmut immunization further conferred increased survival in a murine renal carcinoma HERV-K expressing tumor model and benefitted from anti-PD-1 therapy. Conclusions These results show that the rational redesign of the HERV-K ISD generates a potent immunogen capable of expanding human T cells and mediating mechanistically relevant anti-tumor immunity. We propose that HERV-K-ISDmut antigens represent a promising platform for cancer immunotherapy which should be explored in future clinical trials.
SN - 1479-5876
ER -