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

Publication date: Feb 10, 2020

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.

Fairfax, B.P., Taylor, C.A., Watson, R.A., , Nassiri, Danielli, S., Fang, H., Mah’e, E.A., Cooper, R., , Woodcock, Traill, Z., Al-Mossawi, M.H., Knight, J.C., Klenerman, P., Payne, M., and Middleton. Peripheral CD8 T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma. 25768. 2020 Nat Med.

Concepts Keywords
Agnostic Immune system
Blockade Medicine
CD8 Organ systems
Clonal Medical specialties
Clone Immune checkpoint
Cohort Checkpoint inhibitor
Cytotoxicity
Immune Checkpoint Blockade
Interferon
Magnitude
Melanoma
Memory
Memory Cells
Mitosis
Receptor
RNA Sequencing
Stratification

Semantics

Type Source Name
disease MESH melanoma
pathway KEGG Melanoma

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