{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "University of Oxford"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "name": "S. Sun"
    },
    {
      "name": "M. C. Chan"
    },
    {
      "name": "R. A. Watson"
    },
    {
      "name": "S. MacKay"
    },
    {
      "name": "M. Little"
    },
    {
      "name": "O. Tong"
    },
    {
      "name": "A. Farkas"
    },
    {
      "name": "G. Niu"
    },
    {
      "name": "C. R. Lea"
    },
    {
      "name": "G. Milotay"
    },
    {
      "name": "D. Muldoon"
    },
    {
      "name": "N. Coupe"
    },
    {
      "name": "M. Payne"
    },
    {
      "name": "S. Brian"
    },
    {
      "name": "M. R. Middleton"
    },
    {
      "name": "P. Klenerman"
    },
    {
      "affs": [
        0
      ],
      "name": "B. P. Fairfax"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cr3fmztqaspbq.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.30.26366523",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.30.26366523v1.full",
  "id": "cr3fmztqaspbq",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.30.26366523v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "oncology"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.30.26366523v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cr3fmztqaspbq.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:43Z",
      "native_id": "10.64898/2026.10.30.26366523",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.30.26366523v2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:oncology",
      "subfield": "oncology"
    }
  ],
  "title": "Post-ICB Lymphocyte Stability Following Immune Checkpoint Blockade Is Coupled to Mitochondrial Haplotype and Clinical Outcome in Advanced Melanoma",
  "title_text": "Post-ICB Lymphocyte Stability Following Immune Checkpoint Blockade Is Coupled to Mitochondrial Haplotype and Clinical Outcome in Advanced Melanoma",
  "type": "preprint",
  "updated_at": "2026-11-04T00:21:00Z",
  "url": "https://research.draconitic.com/paper/cr3fmztqaspbq",
  "venue": "medRxiv",
  "versions": []
}