Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.
Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.
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DOI：
10.1016/j.ccell.2021.10.001
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发表时间：
2021-11-08
期刊：
影响因子：
50.3
通讯作者：
TRACERx Renal Consortium
中科院分区：
文献类型：
--
作者：
Au L;Hatipoglu E;Robert de Massy M;Litchfield K;Beattie G;Rowan A;Schnidrig D;Thompson R;Byrne F;Horswell S;Fotiadis N;Hazell S;Nicol D;Shepherd STC;Fendler A;Mason R;Del Rosario L;Edmonds K;Lingard K;Sarker S;Mangwende M;Carlyle E;Attig J;Joshi K;Uddin I;Becker PD;Sunderland MW;Akarca A;Puccio I;Yang WW;Lund T;Dhillon K;Vasquez MD;Ghorani E;Xu H;Spencer C;López JI;Green A;Mahadeva U;Borg E;Mitchison M;Moore DA;Proctor I;Falzon M;Pickering L;Furness AJS;Reading JL;Salgado R;Marafioti T;Jamal-Hanjani M;PEACE Consortium;Kassiotis G;Chain B;Larkin J;Swanton C;Quezada SA;Turajlic S;TRACERx Renal Consortium
ADAPTeR是一项在15例转移性透明细胞肾细胞癌（ccRCC）初治患者（115个多区域肿瘤样本）中进行的nivolumab（抗PD-1）前瞻性II期研究，旨在了解支持治疗反应的机制。基因组分析显示肿瘤分子特征与应答之间无相关性，而ccRCC特异性人内源性逆转录病毒表达与临床应答间接相关。T细胞受体（TCR）分析揭示了应答者中治疗前显著更高数量的扩增的TCR克隆，表明预先存在的免疫力。治疗后维持高度相似的TCR簇可预测应答，表明可能识别相同抗原的T细胞家族的持续抗原接合和存活。在应答者中，nivolumab结合的CD 8 + T细胞扩增并表达GZMK/B。我们的数据表明nivolumab驱动先前扩增的T细胞克隆的维持和替换，但只有维持与应答相关。我们假设，维持和加强预先存在的反应是抗PD-1作用模式的关键要素。在一项前瞻性II期研究中，115份纳武单抗治疗前和治疗后多区域肿瘤样本治疗前扩增的TCR克隆的维持与应答相关扩增的CD 8 + T细胞上调应答者中的GZMB/K HERV表达反映了肿瘤纯度，并与应答间接相关ADAPTeR是一项在转移性透明细胞肾细胞癌初治患者中进行的纳武单抗（抗PD-1）II期研究。通过对治疗前和治疗后多区域肿瘤活检的多组学分析，Au et al.使用批量和单细胞方法评估支持抗PD-1应答和抗性的基因组和肿瘤免疫微环境特征。
ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action. 115 pre- and post-nivolumab multiregion tumor samples in a prospective phase II study Maintenance of pre-treatment expanded TCR clones associates with response Expanded CD8+ T cells upregulate GZMB/K in responders HERV expression reflects tumor purity and indirectly correlates with response ADAPTeR is a phase II study of nivolumab (anti-PD-1) in treatment-naive patients with metastatic clear cell renal cell carcinoma. Through multi-omic analysis of multiregion tumor biopsies taken pre- and post-treatment, Au et al. evaluate genomic and tumor immune microenvironment features underpinning anti-PD-1 response and resistance using bulk and single-cell approaches.
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影响因子：
5.9
作者：
Borcherding N;Vishwakarma A;Voigt AP;Bellizzi A;Kaplan J;Nepple K;Salem AK;Jenkins RW;Zakharia Y;Zhang W
通讯作者：
Zhang W
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影响因子：
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作者：
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通讯作者：
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影响因子：
23.4
作者：
Albiges, Laurence;Powles, Tom;Bex, Axel
通讯作者：
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