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对转移性黑色素瘤抗PD-1疗法的基因组和转录组特征

Willy Hugo¹, Jesse M Zaretsky², Lu Sun¹

¹Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA 90095-1662, USA; David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1662, USA.

|March 22, 2016

概括

高瘤突变负担和BRCA2突变预测了黑色素瘤PD-1治疗的反应. 天生的抗PD-1耐药性 (IPRES) 涉及介酶过渡途径,表明治疗点.

科学领域:

癌症学
免疫学
遗传学

背景情况:

对于黑色素瘤患者来说,PD-1 免疫检查点阻塞具有显著的临床益处.
了解影响抗PD-1治疗的先天敏感性或耐药性的因素对于改善治疗结果至关重要.

研究的目的:

分析治疗前黑色素瘤活检的体质突变和转录.
确定抗PD-1治疗反应的预测生物标志物.
描述与生俱来的抗PD-1耐药性的转录特征 (IPRES).

主要方法:

对体突变和转录的治疗前黑色素瘤活检的分析.
与治疗反应和耐药性相关的转录特征的识别和验证.
黑色素瘤转录形状与MAPK向治疗诱导的形状的比较.

主要成果:

在接受抗PD-1 治疗的黑色素瘤患者中,高突变负载和BRCA2基因突变与改善的生存率相关.
具有先天耐药性的瘤表现出IPRES特征,其特征在于中细胞过渡,细胞粘附,细胞外矩阵重塑,血管新生和伤口愈合中的上调基因.
针对MAPK的治疗诱导了类似的特征,表明交叉抵抗机制.

结论:

瘤突变负担和BRCA2突变是黑色素瘤抗PD-1治疗反应的潜在生物标志物.
IPRES的特征代表了对抗PD-1治疗的先天性耐药性的可针对性机制.
向与IPRES相关的生物过程可能会在黑色素瘤和其他癌症中增强抗PD-1疗效.

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