Deciphering transcriptomic determinants of the divergent link between PD-L1 and immunotherapy efficacy.
Deciphering transcriptomic determinants of the divergent link between PD-L1 and immunotherapy efficacy.
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DOI：
10.1038/s41698-023-00443-3
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发表时间：
2023-09-11
影响因子：
7.9
通讯作者：
中科院分区：
文献类型：
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程序性细胞死亡配体1（PD-L1）表达仍然是预测免疫检查点抑制剂（ICI）反应的最广泛使用的生物标志物，但其预测性差异很大。迫切需要确定导致PD-L1性能变化的因素。在这里，使用来自三项包含1239名患者的独立试验的数据，我们根据肿瘤转录组确定了具有不同PD-L1预测性的癌症子集。在高预测性（PH）组中，在三项试验中，PD-L1+肿瘤比PD-L1-肿瘤显示出更好的总生存期、无进展生存期和ICI的客观缓解率。然而，低预测性（PL）组显示出相反的趋势，PD-L1肿瘤的结局更好。PH组的PD-L1+肿瘤显示ICI优于化疗，而PL组的PD-L1+肿瘤显示两种治疗之间的疗效相当，或显示有利于化疗的相反趋势。无论免疫亚型（免疫增强型或非免疫型）、PD-L1调节机制（适应性或组成性）、肿瘤突变负荷或新抗原负荷如何，这种背景依赖性预测性的观察结果仍然很强。这项工作阐明了在临床决策和试验设计中优化PD-L1表达的途径，尽管这一探索性概念应在大型试验中进一步证实。
Programmed cell death ligand 1 (PD-L1) expression remains the most widely used biomarker for predicting response to immune checkpoint inhibitors (ICI), but its predictiveness varies considerably. Identification of factors accounting for the varying PD-L1 performance is urgently needed. Here, using data from three independent trials comprising 1239 patients, we have identified subsets of cancer with distinct PD-L1 predictiveness based on tumor transcriptome. In the Predictiveness-High (PH) group, PD-L1+ tumors show better overall survival, progression-free survival, and objective response rate with ICI than PD-L1- tumors across three trials. However, the Predictiveness-Low (PL) group demonstrates an opposite trend towards better outcomes for PD-L1- tumors. PD-L1+ tumors from the PH group demonstrate the superiority of ICI over chemotherapy, whereas PD-L1+ tumors from the PL group show comparable efficacy between two treatments or exhibit an opposite trend favoring chemotherapy. This observation of context-dependent predictiveness remains strong regardless of immune subtype (Immune-Enriched or Non-Immune), PD-L1 regulation mechanism (adaptative or constitutive), tumor mutation burden, or neoantigen load. This work illuminates avenues for optimizing the use of PD-L1 expression in clinical decision-making and trial design, although this exploratory concept should be further confirmed in large trials.
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DOI：
10.1038/s41571-021-00546-5
发表时间：
2021-12
期刊：
Nature reviews. Clinical oncology
影响因子：
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作者：
Chen Y;McAndrews KM;Kalluri R
通讯作者：
Kalluri R
DOI：
10.1200/jco.20.01605
发表时间：
2021-03-01
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Borghaei H;Gettinger S;Vokes EE;Chow LQM;Burgio MA;de Castro Carpeno J;Pluzanski A;Arrieta O;Frontera OA;Chiari R;Butts C;Wójcik-Tomaszewska J;Coudert B;Garassino MC;Ready N;Felip E;García MA;Waterhouse D;Domine M;Barlesi F;Antonia S;Wohlleber M;Gerber DE;Czyzewicz G;Spigel DR;Crino L;Eberhardt WEE;Li A;Marimuthu S;Brahmer J
通讯作者：
Brahmer J
影响因子：
20.4
作者：
Herbst, Roy S.;Garon, Edward B.;Baas, Paul
通讯作者：
Baas, Paul
影响因子：
30.5
作者：
Blackburn, Shawn D.;Shin, Haina;Haining, W. Nicholas;Zou, Tao;Workman, Creg J.;Polley, Antonio;Betts, Michael R.;Freeman, Gordon J.;Vignali, Dario A. A.;Wherry, E. John
通讯作者：
Wherry, E. John
DOI：
10.1126/science.aar3593
发表时间：
2018-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Cristescu R;Mogg R;Ayers M;Albright A;Murphy E;Yearley J;Sher X;Liu XQ;Lu H;Nebozhyn M;Zhang C;Lunceford JK;Joe A;Cheng J;Webber AL;Ibrahim N;Plimack ER;Ott PA;Seiwert TY;Ribas A;McClanahan TK;Tomassini JE;Loboda A;Kaufman D
通讯作者：
Kaufman D