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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.

Original publication

DOI

10.1038/s41591-019-0734-6

Type

Journal article

Journal

Nat Med

Publication Date

02/2020

Volume

26

Pages

193 - 199

Keywords

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