Nature medicine, 2020-02, Vol.26 (2), p.193-199
2020
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- Autor(en) / Beteiligte
- Titel
- Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma
- Ist Teil von
- Nature medicine, 2020-02, Vol.26 (2), p.193-199
- Ort / Verlag
- New York: Nature Publishing Group US
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1078-8956eISSN: 1546-170XDOI: 10.1038/s41591-019-0734-6Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_7611047
- Format
- –
- Schlagworte
- 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