Endogenous Retrovirus-Targeted Immunotherapy for Non-Small Cell Lung Cancer Supported by Cellular HERV-K Expression, Dependency and Efficacy of ERV Therapy in a Murine Model
4 affiliations
- 1HERVolution Therapeutics, Symbion, 2000 Frederiksberg, Denmark
- 2MDxCORE, Copenhagen University Hospital (Rigshospitalet), 2100 Copenhagen, Denmark
- 3Department of Biomedical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
- 4Department of Immunology and Microbiology, University of Copenhagen, 2200 Copenhagen, Denmark
Abstract
Human endogenous retrovirus-K (HERV-K/HML-2) has been associated with non-small cell lung cancer (NSCLC), but its functional relevance and the potential for HERV-directed immunotherapy remains unresolved. Here, we characterized HERV-K expression across 207 advanced NSCLC patient biopsies by total RNA-seq observing widespread expression of HERV-K Gag and Env antigen encoding sequences. The Env-ORF that disrupted HERV-K102 was strongly associated with interferon and antigen-presenting programs, identifying it as a marker of an immune-activated tumor state. shRNA-mediated knockdown of HERV-K in five NSCLC cell lines with distinct driver mutations impaired proliferation and survival. In separate experiments, exposure of these cell lines to treatment-related stressors, including cytokines (TNF-α and IFN-γ) and chemotherapy, revealed dynamic patterns of HERV-K protein accumulation with antigen expression retained, and in some cases increased. Immunotherapeutic targeting was performed using the ASB-XIV mouse NSCLC cell line and a murine ERV surrogate antigen using adenovirus to express murine leukemia virus (MLV) antigen on a mouse β-retroviral particle structurally related to HERV-K. This immunization was able to elicit significant protection against tumor challenge and additive benefit with anti-PD-L1 in therapeutic treatment, establishing proof-of-concept for ERV-targeted immunotherapy in a murine surrogate system rather than direct evidence of HERV-K-targeted efficacy. Our findings suggest an important role of HERV-K in NSCLC immunobiology and that adaptive immunity targeting HERV-K should be explored in the treatment of NSCLC patients.
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BibTeX
@article{perezpenco2026endogenous,
title = {{Endogenous Retrovirus-Targeted Immunotherapy for Non-Small Cell Lung Cancer Supported by Cellular HERV-K Expression, Dependency and Efficacy of ERV Therapy in a Murine Model}},
author = {Maria Perez-Penco and Tara Elizabeth Scott and Emilie Sofie Engdal and Cristina Picon Jara and Gabriel Mira González and Lea Klingenber Barfod and Kristoffer Staal Rohrberg and Frederik Otzen Bagger and Lasse Neukirch and Anne-Marie Carola Andersson and Peter Johannes Holst},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219717},
url = {https://www.mdpi.com/1422-0067/27/21/9717},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Endogenous Retrovirus-Targeted Immunotherapy for Non-Small Cell Lung Cancer Supported by Cellular HERV-K Expression, Dependency and Efficacy of ERV Therapy in a Murine Model
AU - Maria Perez-Penco
AU - Tara Elizabeth Scott
AU - Emilie Sofie Engdal
AU - Cristina Picon Jara
AU - Gabriel Mira González
AU - Lea Klingenber Barfod
AU - Kristoffer Staal Rohrberg
AU - Frederik Otzen Bagger
AU - Lasse Neukirch
AU - Anne-Marie Carola Andersson
AU - Peter Johannes Holst
PY - 2026
DA - 2026/10/29
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219717
UR - https://www.mdpi.com/1422-0067/27/21/9717
AB - Human endogenous retrovirus-K (HERV-K/HML-2) has been associated with non-small cell lung cancer (NSCLC), but its functional relevance and the potential for HERV-directed immunotherapy remains unresolved. Here, we characterized HERV-K expression across 207 advanced NSCLC patient biopsies by total RNA-seq observing widespread expression of HERV-K Gag and Env antigen encoding sequences. The Env-ORF that disrupted HERV-K102 was strongly associated with interferon and antigen-presenting programs, identifying it as a marker of an immune-activated tumor state. shRNA-mediated knockdown of HERV-K in five NSCLC cell lines with distinct driver mutations impaired proliferation and survival. In separate experiments, exposure of these cell lines to treatment-related stressors, including cytokines (TNF-α and IFN-γ) and chemotherapy, revealed dynamic patterns of HERV-K protein accumulation with antigen expression retained, and in some cases increased. Immunotherapeutic targeting was performed using the ASB-XIV mouse NSCLC cell line and a murine ERV surrogate antigen using adenovirus to express murine leukemia virus (MLV) antigen on a mouse β-retroviral particle structurally related to HERV-K. This immunization was able to elicit significant protection against tumor challenge and additive benefit with anti-PD-L1 in therapeutic treatment, establishing proof-of-concept for ERV-targeted immunotherapy in a murine surrogate system rather than direct evidence of HERV-K-targeted efficacy. Our findings suggest an important role of HERV-K in NSCLC immunobiology and that adaptive immunity targeting HERV-K should be explored in the treatment of NSCLC patients.
SN - 1422-0067
ER -