Peripheral CD8(+) T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma.
Peripheral CD8(+) T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma.
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DOI：
10.1038/s41591-019-0734-6
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发表时间：
2020-02
期刊：
影响因子：
82.9
通讯作者：
Middleton MR
中科院分区：
文献类型：
--
作者：
Fairfax BP;Taylor CA;Watson RA;Nassiri I;Danielli S;Fang H;Mahé EA;Cooper R;Woodcock V;Traill Z;Al-Mossawi MH;Knight JC;Klenerman P;Payne M;Middleton MR
PD-1和CTLA-4的免疫检查点阻断（ICB）治疗转移性黑色素瘤（MM）具有不同的治疗益处。为了在外周样本中探索这一点，我们表征了接受抗PD-1单药（sICB）或与抗CTLA-4（cICB）联合治疗的MM患者队列中的CD 8 + T细胞基因表达。尽管对sICB和cICB的CD 8+转录应答涉及共享的基因集，但cICB应答的幅度超过4倍，优先诱导有丝分裂和干扰素相关基因。来自具有持久临床益处的患者的早期样品证明了T细胞受体（TCR）编码基因的过表达。通过对TCR克隆性作图，我们发现应答患者在治疗后比无应答患者或对照具有更多的大克隆（那些占据>0.5%的库的克隆），并且这与效应记忆T细胞百分比相关。8个治疗后样本的单细胞RNA测序表明，大克隆过度表达涉及细胞毒性和效应记忆T细胞特征的基因，包括CCL 4、GNLY和NKG 7。MM患者对ICB的6个月临床应答与治疗后21天的大CD 8 + T细胞克隆计数相关，且与克隆特异性无关，表明ICB后外周CD 8+克隆性可提供有关长期治疗应答的信息，并可能促进治疗分层。
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.
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影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
WGCNA：用于加权相关网络分析的 R 包。
影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
DOI：
10.1016/s1470-2045(18)30078-0
发表时间：
2018-03
期刊：
The Lancet. Oncology
影响因子：
--
作者：
McQuade JL;Daniel CR;Hess KR;Mak C;Wang DY;Rai RR;Park JJ;Haydu LE;Spencer C;Wongchenko M;Lane S;Lee DY;Kaper M;McKean M;Beckermann KE;Rubinstein SM;Rooney I;Musib L;Budha N;Hsu J;Nowicki TS;Avila A;Haas T;Puligandla M;Lee S;Fang S;Wargo JA;Gershenwald JE;Lee JE;Hwu P;Chapman PB;Sosman JA;Schadendorf D;Grob JJ;Flaherty KT;Walker D;Yan Y;McKenna E;Legos JJ;Carlino MS;Ribas A;Kirkwood JM;Long GV;Johnson DB;Menzies AM;Davies MA
通讯作者：
Davies MA
影响因子：
12.3
作者：
Lun AT;Bach K;Marioni JC
通讯作者：
Marioni JC