Journal Article

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

Middleton, Mark R., Woodcock, Victoria, Fairfax, Benjamin P., Traill, Zoe, Nassiri, Isar, Klenerman, Paul, Al-Mossawi, M. Hussein, Taylor, Chelsea A., Cooper, Rosalin, Watson, Robert A., Danielli, Sara, Fang, Hai, Mahé, Elise A., Knight, Julian C., Payne, Miranda

2020

Overview

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. Transcriptomic analysis of peripheral CD8 + T cells in a cohort of patients with metastatic melanoma receiving checkpoint inhibitors shows that the number of large clones early post-treatment is strongly associated with six-month clinical outcome.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/114/2114 / 631/250/251 / 692/308/409 / 692/699/67/1813/1634 / Adult / Antibodies - therapeutic use / Antigens, Differentiation, T-Lymphocyte - genetics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carbon tetrachloride / CD8 antigen / CD8-Positive T-Lymphocytes - cytology / Cell Proliferation / Chemokine CCL4 - genetics / Cloning / Cohort Studies / CTLA-4 Antigen - immunology / CTLA-4 protein / Cytotoxicity / Effector cells / Female / Gene expression / Gene Expression Profiling / Gene mapping / Gene sequencing / Genes / Humans / Immune checkpoint / Immune System / Immunological memory / Immunotherapy - methods / Infectious Diseases / Interferon / Letter / Lymphocytes / Lymphocytes T / Male / Mapping / Melanoma / Melanoma - immunology / Melanoma - therapy / Membrane Proteins - genetics / Memory cells / Metabolic Diseases / Metastases / Metastasis / Middle Aged / Mitosis / Molecular Medicine / Neoplasm Metastasis / Neurosciences / Patients / PD-1 protein / Programmed Cell Death 1 Receptor - metabolism / Receptors, Antigen, T-Cell - genetics / Ribonucleic acid / RNA / Single-Cell Analysis / T cell receptors / Toxicity / Transcription / Transcriptomics / Young Adult