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
2020-02-13   阅读:250   来源:自然

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》。

研究人员表示,PD-1和CTLA-4的免疫检查点阻断(ICB)治疗转移性黑色素瘤(MM)具有不同的治疗效果。
 
为了在外周样本中探索这一点,研究人员表征了一组单独接受抗PD-1(sICB)或与抗CTLA-4(cICB)结合使用的MM患者的CD8+T细胞基因表达。尽管对sICB和cICB的CD8+转录反应涉及一个共同的基因集,但cICB反应的强度却高四倍以上,并优先诱导有丝分裂和干扰素相关基因。具有持久临床益处的患者早期样本证明了T细胞受体编码基因的过表达。通过绘制T细胞受体克隆图谱,研究人员发现相应的患者与非相应的患者或对照组相比,治疗后的克隆数量更多(占全部的0.5%以上),这与效应记忆T细胞的百分比有关。八个治疗后样品的单细胞RNA测序表明,大量克隆过表达了涉及细胞毒性和效应记忆T细胞特征的基因,包括CCL4、GNLY和NKG7。MM患者对ICB的6个月临床反应与治疗后21天的CD8+T细胞克隆计数有关,并且与克隆特异性无关,这表明ICB后外周CD8+克隆性可以提供有关长期治疗反应,并且可能促进治疗分层。
 
附:英文原文

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

Issue&Volume: 2020-02-10

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.

DOI: 10.1038/s41591-019-0734-6

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