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.
- B cells and tertiary lymphoid structures promote immunotherapy response.
- Mechanisms of checkpoint inhibition induced adverse events.
- APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy.
- Tumor heterogeneity and clonal cooperation influence the immune selection of IFN-γ-signaling mutant cancer cells.
- Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.
- Single-cell analysis reveals new evolutionary complexity in uveal melanoma.
- DENDRO: genetic heterogeneity profiling and subclone detection by single-cell RNA sequencing.
- Comprehensive analysis of tumor necrosis factor receptor TNFRSF9 (4-1BB) DNA methylation with regard to molecular and clinicopathological features, immune infiltrates, and response prediction to immunotherapy in melanoma.