Immune Checkpoint Blockade Sensitivity Is Linked to Endogenous Retroelement Transcriptional Changes in Cancer
9 affiliations
- 1Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
- 2University of Toronto, Toronto, Canada.
- 3Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
- 4School of Computer Science, University of Guelph, Guelph, Canada.
- 5Biostatistics Department, University Health Network, Toronto, Canada.
- 6Department of Medical Biophysics, University of Toronto, Toronto, Canada.
- 7Ontario Institute for Cancer Research, Toronto, Canada.
- 8Structural Genomics Consortium, University Health Network, Toronto, Canada.
- 9School of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
Abstract
Endogenous retrotransposable elements (ERE) can modulate immune responses. We explored ERE transcription in relation to response to immune checkpoint inhibition in advanced solid tumors. ERE expression was measured in pre- and on-treatment samples from patients treated in a clinical trial with pembrolizumab. We evaluated immune cell infiltration and correlated ERE expression with interferon (IFN)-stimulated gene profiles and cytolytic activity. Two independent datasets were retrospectively analyzed as external validation. ERE transcription, notably Alu repetitive elements followed by long interspersed nuclear elements (LINE), is upregulated in immunotherapy responders, and higher ERE expression correlates with durable clinical benefit and improved long-term outcomes. In responders, this dynamic increase correlates with CD8+ T-cell infiltration and cytolytic activity, particularly during treatment. A trend toward increased A-to-I RNA editing was observed in responders. External validation in melanoma and non–small cell lung cancer cohorts confirmed a consistent pattern in ERE transcription. Therefore, ERE transcription is emerging as a potential biomarker for personalized immunotherapy in solid tumors.
Related
- 951 Engineered tumor-homing bacteria enable systemic combination immune checkpoint blockade and cytokine immunotherapy
- Patient-Derived Melanoma Organoids Preserve Tumor-Immune Heterogeneity and Reveal Context-Dependent Responses to Immune Checkpoint Blockade
- Redox Storm in the Tumor Microenvironment (ΤΜΕ): Multifaceted Redox Injury and Immunometabolic Reprogramming Induced by Immune Checkpoint Blockade in B16F10 Melanoma: An Ultrastructural Study of the Peritumoral Interface
- Context-dependent value of HLA class I diversity in advanced non-small cell lung cancer treated with immune checkpoint blockade
- 733 Macrophage-dendritic cell-T-cell tetrads orchestrate antitumor immunity and response to checkpoint blockade
BibTeX
@article{herrera2026immune,
title = {{Immune Checkpoint Blockade Sensitivity Is Linked to Endogenous Retroelement Transcriptional Changes in Cancer}},
author = {Mercedes Herrera and Sajid A. Marhon and Zhihui Amy Liu and Helen Loo and Farnoosh Abbas-Aghababazadeh and Jeff P. Bruce and David Chen and Emily Van de Laar and Helen Chow and Philippe L. Bedard and Albiruni R. Abdul Razak and Anna Spreafico and Marcus O. Butler and Stephanie Lheureux and Trevor J. Pugh and Benjamin Haibe-Kains and Lillian L. Siu and Daniel D. De Carvalho and Pavlina Spiliopoulou},
journal = {Cancer Immunology Research},
year = {2026},
month = aug,
doi = {10.1158/2326-6066.cir-26-0365},
url = {https://doi.org/10.1158/2326-6066.cir-26-0365},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Immune Checkpoint Blockade Sensitivity Is Linked to Endogenous Retroelement Transcriptional Changes in Cancer
AU - Mercedes Herrera
AU - Sajid A. Marhon
AU - Zhihui Amy Liu
AU - Helen Loo
AU - Farnoosh Abbas-Aghababazadeh
AU - Jeff P. Bruce
AU - David Chen
AU - Emily Van de Laar
AU - Helen Chow
AU - Philippe L. Bedard
AU - Albiruni R. Abdul Razak
AU - Anna Spreafico
AU - Marcus O. Butler
AU - Stephanie Lheureux
AU - Trevor J. Pugh
AU - Benjamin Haibe-Kains
AU - Lillian L. Siu
AU - Daniel D. De Carvalho
AU - Pavlina Spiliopoulou
PY - 2026
DA - 2026/08/13
JO - Cancer Immunology Research
DO - 10.1158/2326-6066.cir-26-0365
UR - https://doi.org/10.1158/2326-6066.cir-26-0365
AB - Endogenous retrotransposable elements (ERE) can modulate immune responses. We explored ERE transcription in relation to response to immune checkpoint inhibition in advanced solid tumors. ERE expression was measured in pre- and on-treatment samples from patients treated in a clinical trial with pembrolizumab. We evaluated immune cell infiltration and correlated ERE expression with interferon (IFN)-stimulated gene profiles and cytolytic activity. Two independent datasets were retrospectively analyzed as external validation. ERE transcription, notably Alu repetitive elements followed by long interspersed nuclear elements (LINE), is upregulated in immunotherapy responders, and higher ERE expression correlates with durable clinical benefit and improved long-term outcomes. In responders, this dynamic increase correlates with CD8+ T-cell infiltration and cytolytic activity, particularly during treatment. A trend toward increased A-to-I RNA editing was observed in responders. External validation in melanoma and non–small cell lung cancer cohorts confirmed a consistent pattern in ERE transcription. Therefore, ERE transcription is emerging as a potential biomarker for personalized immunotherapy in solid tumors.
SN - 2326-6066
SN - 2326-6074
ER -