小柯机器人

近日，澳大利亚悉尼大学Georgina V. Long及其课题组完成检查点抑制剂治疗黑色素瘤的多组学分析。2021年12月23日，《癌细胞》杂志在线发表了这项成果。

研究人员同时检查了77名接受抗PD-1治疗或不接受抗CTLA-4治疗的晚期皮肤黑色素瘤患者基线肿瘤的全基因组、转录组、甲基组和免疫细胞浸润情况。结果表明，高肿瘤突变负荷（TMB）、新抗原负荷、IFNγ相关基因的表达、程序性死亡配体表达、低PSMB8甲基化（因此高表达）以及肿瘤微环境中的T细胞与免疫疗法的反应有关。没有特定的突变与治疗反应相关。结合TMB和IFNγ相关基因表达的多变量模型可以有力地预测反应（89%的敏感性，53%的特异性，曲线下面积[AUC]，0.84）；具有高TMB和高IFNγ特征的肿瘤对免疫疗法的反应最好。

这个模型在一个独立的队列中得到验证（80%的敏感性，59%的特异性，AUC，0.79）。除了JAK3功能缺失的突变外，对于那些没有预测反应的患者，没有明显的生物机制可以清楚地解释他们的离群状态，这与免疫治疗反应的瘤内和瘤间异质性相一致。

附：英文原文

Title: Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance

Author: Felicity Newell, Ines Pires da Silva, Peter A. Johansson, Alexander M. Menzies, James S. Wilmott, Venkateswar Addala, Matteo S. Carlino, Helen Rizos, Katia Nones, Jarem J. Edwards, Vanessa Lakis, Stephen H. Kazakoff, Pamela Mukhopadhyay, Peter M. Ferguson, Conrad Leonard, Lambros T. Koufariotis, Scott Wood, Christian U. Blank, John F. Thompson, Andrew J. Spillane, Robyn P.M. Saw, Kerwin F. Shannon, John V. Pearson, Graham J. Mann, Nicholas K. Hayward, Richard A. Scolyer, Nicola Waddell, Georgina V. Long

Issue&Volume: 2021-12-23

Abstract: We concurrently examine the whole genome, transcriptome, methylome, and immune cellinfiltrates in baseline tumors from 77 patients with advanced cutaneous melanoma treatedwith anti-PD-1 with or without anti-CTLA-4. We show that high tumor mutation burden(TMB), neoantigen load, expression of IFNγ-related genes, programmed death ligandexpression, low PSMB8 methylation (therefore high expression), and T cells in the tumor microenvironmentare associated with response to immunotherapy. No specific mutation correlates withtherapy response. A multivariable model combining the TMB and IFNγ-related gene expressionrobustly predicts response (89% sensitivity, 53% specificity, area under the curve[AUC], 0.84); tumors with high TMB and a high IFNγ signature show the best responseto immunotherapy. This model validates in an independent cohort (80% sensitivity,59% specificity, AUC, 0.79). Except for a JAK3 loss-of-function mutation, for patients who did not respond as predicted there isno obvious biological mechanism that clearly explained their outlier status, consistentwith intratumor and intertumor heterogeneity in response to immunotherapy.

DOI: 10.1016/j.ccell.2021.11.012

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00612-7

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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