英国牛津大学Benjamin P. Fairfax研究小组发现，转移性黑色素瘤患者外周CD8+T细胞特征与对免疫检查点阻断的持久反应相关。该研究2020年2月10日发表于国际一流学术期刊《自然—医学》。
Title: Peripheral CD8 + T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma
Author: Benjamin P. Fairfax, Chelsea A. Taylor, Robert A. Watson, Isar Nassiri, Sara Danielli, Hai Fang, Elise A. Mah, Rosalin Cooper, Victoria Woodcock, Zoe Traill, M. Hussein Al-Mossawi, Julian C. Knight, Paul Klenerman, Miranda Payne, Mark R. Middleton
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 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 21d 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.