Post-ICB Lymphocyte Stability Following Immune Checkpoint Blockade Is Coupled to Mitochondrial Haplotype and Clinical Outcome in Advanced Melanoma
- 1University of Oxford
Abstract
Early biomarkers of durable response to immune checkpoint blockade (ICB) are urgently needed. We identify lymphocyte stability (LS) - preservation of peripheral lymphocyte counts after one cycle of ICB - as an on-treatment predictor of overall survival (OS) in metastatic melanoma (MM): patients with unstable lymphocyte counts (LS-U; post-ICB/baseline [≤]0.8) have markedly increased risk of death. Metabolic profiling of patient T cells demonstrates ICB enhancement of mitochondrial bioenergetics, whilst CD8+ T cells from LS-U patients mount an exaggerated transcriptional response to ICB incorporating upregulation of mitochondrial pathways. Given these findings we assessed the relationship of LS with mitochondrial haplogroup, revealing carriage of haplogroup T (HG-T), present in ~10% of white British individuals, is associated with both LS-U and impaired OS, with mediation analysis implicating LS mediation. HG-T carriers have higher CD8+ T-cell pre-treatment mitochondrially encoded transcript abundance and, in paired scRNA-seq data, fewer progenitor-exhausted cells, ICB hyperresponsivity, apoptotic program induction and reduced clonal persistence, consistent with baseline mitochondrial priming. These findings position LS as a clinically accessible marker of ICB outcome linked to inherited mitochondrial variation.
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BibTeX
@misc{sun2026posticb,
title = {{Post-ICB Lymphocyte Stability Following Immune Checkpoint Blockade Is Coupled to Mitochondrial Haplotype and Clinical Outcome in Advanced Melanoma}},
author = {S. Sun and M. C. Chan and R. A. Watson and S. MacKay and M. Little and O. Tong and A. Farkas and G. Niu and C. R. Lea and G. Milotay and D. Muldoon and N. Coupe and M. Payne and S. Brian and M. R. Middleton and P. Klenerman and B. P. Fairfax},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.26366523},
url = {https://www.medrxiv.org/content/10.64898/2026.10.30.26366523v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Post-ICB Lymphocyte Stability Following Immune Checkpoint Blockade Is Coupled to Mitochondrial Haplotype and Clinical Outcome in Advanced Melanoma
AU - S. Sun
AU - M. C. Chan
AU - R. A. Watson
AU - S. MacKay
AU - M. Little
AU - O. Tong
AU - A. Farkas
AU - G. Niu
AU - C. R. Lea
AU - G. Milotay
AU - D. Muldoon
AU - N. Coupe
AU - M. Payne
AU - S. Brian
AU - M. R. Middleton
AU - P. Klenerman
AU - B. P. Fairfax
PY - 2026
DA - 2026/10/30
PB - medRxiv
DO - 10.64898/2026.10.30.26366523
UR - https://www.medrxiv.org/content/10.64898/2026.10.30.26366523v1
AB - Early biomarkers of durable response to immune checkpoint blockade (ICB) are urgently needed. We identify lymphocyte stability (LS) - preservation of peripheral lymphocyte counts after one cycle of ICB - as an on-treatment predictor of overall survival (OS) in metastatic melanoma (MM): patients with unstable lymphocyte counts (LS-U; post-ICB/baseline [≤]0.8) have markedly increased risk of death. Metabolic profiling of patient T cells demonstrates ICB enhancement of mitochondrial bioenergetics, whilst CD8+ T cells from LS-U patients mount an exaggerated transcriptional response to ICB incorporating upregulation of mitochondrial pathways. Given these findings we assessed the relationship of LS with mitochondrial haplogroup, revealing carriage of haplogroup T (HG-T), present in ~10% of white British individuals, is associated with both LS-U and impaired OS, with mediation analysis implicating LS mediation. HG-T carriers have higher CD8+ T-cell pre-treatment mitochondrially encoded transcript abundance and, in paired scRNA-seq data, fewer progenitor-exhausted cells, ICB hyperresponsivity, apoptotic program induction and reduced clonal persistence, consistent with baseline mitochondrial priming. These findings position LS as a clinically accessible marker of ICB outcome linked to inherited mitochondrial variation.
ER -