Fairfax et al. show that large TCR clone counts (>5% of the total number of clones) in peripheral CD8+ T cells are predictive of positive response to checkpoint therapy in patients with metastatic melanoma. Transcriptomic analysis revealed overexpression of T cell receptor genes in early samples (day 21) from ICB-responding patients, which was associated with higher number of discrete large clones. Patients with a higher number of large clones in circulation demonstrated increased progression-free and overall survival. Single-cell sequencing showed that cells from large clones display cytotoxic gene overexpression and effector memory phenotypes.
Contributed by Shishir Pant
Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples, we characterized CD8(+) T cell gene expression across a cohort of patients with MM receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8(+) transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over fourfold greater, with preferential induction of mitosis- and interferon-related genes. Early samples from patients with durable clinical benefit demonstrated overexpression of T cell receptor-encoding genes. By mapping T cell receptor clonality, we find that responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates that large clones overexpress genes implicated in cytotoxicity and characteristic of effector memory T cells, including CCL4, GNLY and NKG7. The 6-month clinical response to ICB in patients with MM is associated with the large CD8(+) T cell clone count 21 d after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8(+) clonality can provide information regarding long-term treatment response and, potentially, facilitate treatment stratification.
Author Info: (1) MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. benjamin.fairfax@oncology.ox.ac.uk. Department of Oncology, University of Oxford & Oxford Canc
Author Info: (1) MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. benjamin.fairfax@oncology.ox.ac.uk. Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. benjamin.fairfax@oncology.ox.ac.uk. NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. benjamin.fairfax@oncology.ox.ac.uk. (2) MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (3) MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (4) MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (5) Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (6) Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (7) MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (8) MRC-Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (9) Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (10) Department of Radiology, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (11) Botnar Research Centre, NDORMS, University of Oxford, Oxford, UK. (12) NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (13) NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK. (14) Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. (15) Department of Oncology, University of Oxford & Oxford Cancer Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK. NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
