Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma

Nat Med. 2020 Feb;26(2):193-199. doi: 10.1038/s41591-019-0734-6. Epub 2020 Feb 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antibodies / therapeutic use
  • Antigens, Differentiation, T-Lymphocyte / genetics
  • CD8-Positive T-Lymphocytes / cytology*
  • CTLA-4 Antigen / immunology*
  • Cell Proliferation
  • Chemokine CCL4 / genetics
  • Cohort Studies
  • Female
  • Gene Expression Profiling
  • Humans
  • Immune System
  • Immunotherapy / methods*
  • Male
  • Melanoma / immunology*
  • Melanoma / therapy*
  • Membrane Proteins / genetics
  • Middle Aged
  • Neoplasm Metastasis
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Single-Cell Analysis
  • Young Adult


  • Antibodies
  • Antigens, Differentiation, T-Lymphocyte
  • CCL4 protein, human
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Chemokine CCL4
  • GNLY protein, human
  • Membrane Proteins
  • NKG7 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell