Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition.
Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition.
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DOI：
10.1016/j.cell.2021.01.002
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发表时间：
2021-02-04
期刊：
影响因子：
64.5
通讯作者：
Swanton C
中科院分区：
文献类型：
--
作者：
Litchfield K;Reading JL;Puttick C;Thakkar K;Abbosh C;Bentham R;Watkins TBK;Rosenthal R;Biswas D;Rowan A;Lim E;Al Bakir M;Turati V;Guerra-Assunção JA;Conde L;Furness AJS;Saini SK;Hadrup SR;Herrero J;Lee SH;Van Loo P;Enver T;Larkin J;Hellmann MD;Turajlic S;Quezada SA;McGranahan N;Swanton C
检查点抑制剂（CPIs）增强适应性免疫。系统的泛肿瘤分析可能揭示肿瘤细胞内在和微环境特征支持CPI致敏的相对重要性。在这里，我们整理了7种肿瘤类型中> 1，000名CPI治疗患者的全外显子组和转录组数据，利用标准化的生物信息学工作流程和临床结果标准来验证CPI致敏的多变量预测因子。克隆性肿瘤突变负荷（TMB）是CPI反应的最强预测因子，其次是总TMB和CXCL 9表达。亚克隆TMB，体细胞拷贝改变负担，和组织相容性白细胞抗原（HLA）的进化分歧未能达到泛癌症的意义。二核苷酸变体被鉴定为与自由基氨基酸取代和增强的肽疏水性/免疫原性相关的免疫原性表位的来源。拷贝数分析揭示了先前功能证据支持的CPI结果的两个额外决定因素：与应答相关的9 q34（TRAF 2）缺失和与耐药相关的CCND 1扩增。最后，克隆新抗原反应性CD 8肿瘤浸润淋巴细胞（TIL）的单细胞RNA测序（RNA-seq），结合CPI反应性肿瘤的批量RNA-seq分析，将CCR 5和CXCL 13鉴定为CPI敏感性的T细胞内在标志物。> 1，000例CPI治疗病例的大规模荟萃分析，具有外显子组/转录组数据克隆TMB和CXCL 9/CXCL 13表达是CPI反应的最强预测因子CPI反应的多变量预测因子显著优于TMB 9 q34缺失和CCND 1扩增是CPI反应的额外决定因素全外显子组和转录组荟萃分析超过1，000例接受免疫检查点阻断治疗的7种肿瘤类型的患者突出了多变量预测模型的潜力，该模型考虑了肿瘤和T细胞内在的反应机制。
Checkpoint inhibitors (CPIs) augment adaptive immunity. Systematic pan-tumor analyses may reveal the relative importance of tumor-cell-intrinsic and microenvironmental features underpinning CPI sensitization. Here, we collated whole-exome and transcriptomic data for >1,000 CPI-treated patients across seven tumor types, utilizing standardized bioinformatics workflows and clinical outcome criteria to validate multivariable predictors of CPI sensitization. Clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and CXCL9 expression. Subclonal TMB, somatic copy alteration burden, and histocompatibility leukocyte antigen (HLA) evolutionary divergence failed to attain pan-cancer significance. Dinucleotide variants were identified as a source of immunogenic epitopes associated with radical amino acid substitutions and enhanced peptide hydrophobicity/immunogenicity. Copy-number analysis revealed two additional determinants of CPI outcome supported by prior functional evidence: 9q34 (TRAF2) loss associated with response and CCND1 amplification associated with resistance. Finally, single-cell RNA sequencing (RNA-seq) of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs), combined with bulk RNA-seq analysis of CPI-responding tumors, identified CCR5 and CXCL13 as T-cell-intrinsic markers of CPI sensitivity. Large-scale meta-analysis of >1,000 CPI-treated cases with exome/transcriptome data Clonal TMB and CXCL9/CXCL13 expression are the strongest predictors of CPI response A multivariable predictor of CPI response significantly outperforms TMB 9q34 loss and CCND1 amplification are additional determinants of CPI response A whole-exome and transcriptome meta-analysis of over 1,000 patients treated with immune checkpoint blockade across seven tumor types highlights the potential of multivariable prediction models that consider both tumor- and T-cell-intrinsic mechanisms of response.
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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
影响因子：
11.2
作者：
Endesfelder D;Burrell R;Kanu N;McGranahan N;Howell M;Parker PJ;Downward J;Swanton C;Kschischo M
通讯作者：
Kschischo M
影响因子：
10.7
作者：
Dagan, T;Talmor, Y;Graur, D
通讯作者：
Graur, D
影响因子：
2.9
作者：
Bravata, DM;Olkin, I
通讯作者：
Olkin, I
影响因子：
20.3
作者：
Chapuy, Bjoern;Stewart, Chip;Shipp, Margaret A.
通讯作者：
Shipp, Margaret A.