Post-ICB Lymphocyte Stability Following Immune Checkpoint Blockade Is Coupled to Mitochondrial Haplotype and Clinical Outcome in Advanced Melanoma

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.