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

Abstract

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 MM patients 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 four-fold greater, with preferential induction of mitosis and interferon related genes. Early samples from patients with durable clinical benefit demonstrated over-expression of T cell receptor (TCR) encoding genes. By mapping TCR clonality we find 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 large clones over-express genes implicated in cytotoxicity and characteristic of effector memory T cells including CCL4, GNLY, and NKG7. The six-month clinical response to ICB in MM patients is associated with the large CD8+ T cell clone count 21 days 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.