为何PD-1对有些病人不起作用？

来源：生物谷

突变负荷或可预测病人的生存率，但无法预测对anti-PD-1免疫疗法的应答情况

　　能够对anti-PD-1免疫疗法产生应答的黑色素瘤病人存在BRCA2基因突变富集的情况
　　有anti-PD-1天然抗性(IPRES)的黑色素瘤存在一种特定的转录特征
　　根据IPRES定义了针对不同晚期癌症类型的转录组学分组

　　近日，来自美国加州大学洛杉矶分校的研究人员在国际学术期刊Cell上发表了一项最新研究进展，在这篇文章中他们利用组学的方法分析了转移性黑色素瘤病人在anti-PD-1免疫疗法治疗过程中的基因组学和转录组学特征。
　　PD-1免疫检查点阻断是一种非常有效同时非常具有前景的肿瘤免疫治疗方法，这种方法为黑色素瘤病人提供了非常显著的临床效果。但是也有一些病人对该方法存在天然抗性，病人对anti-PD-1免疫疗法的不同应答情况可能对应着不同的基因组学和转录组学特征。
　　在该项研究中，研究人员分析了黑色素瘤病人治疗前活检样本的体细胞突变组和转录组，希望发现一些可能影响病人对anti-PD-1疗法的天然敏感性和抵抗性的因素。结果表明高突变负荷与病人生存率改善存在相关性，同时产生治疗应答效应的病人肿瘤组织中还存在DNA修复基因BRCA2的突变富集情况。
　　研究人员发现具有天然抗性(IPRES)的肿瘤本身存在一种转录特征,参与多个生物学过程调节的基因都出现了表达上调的情况，这些生物学过程包括间充质转化，细胞黏附，细胞外基质重塑，血管生成以及伤口愈合。特别值得注意的是，MAPK靶向疗法能够在黑色素瘤中诱导类似的转录特征出现，这也就意味着MAPK抑制剂疗法可能与anti-PD-1疗法存在交叉抵抗的情况。
　　除此之外，研究人员还在其他一些独立的肿瘤队列中进行了验证，并针对不同晚期癌症类型定义了转录组学的分组。
　　综上所述，削弱隐藏在IPRES背后的生物学过程可能有助于提高黑色素瘤和其他癌症病人对anti-PD-1疗法的应答情况。

DOI:http://dx.doi.org/10.1016/j.cell.2016.02.065
Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in
Metastatic Melanoma
Willy Hugo9, Jesse M. Zaretsky9, Lu Sun, Chunying Song, Blanca Homet Moreno,
Siwen Hu-Lieskovan, Beata Berent-Maoz, Jia Pang, Bartosz Chmielowski,Grace
Cherry, Elizabeth Seja, Shirley Lomeli, Xiangju Kong, Mark C. Kelley, Jeffrey A.
Sosman, Douglas B. Johnson, Antoni Ribas, Roger S. Lo
PD-1 immune checkpoint blockade provides significant clinical benefits for
melanoma patients. We analyzed the somatic mutanomes and transcriptomes of
pretreatment melanoma biopsies to identify factors that may influence innate
sensitivity or resistance to anti-PD-1 therapy. We find that overall high
mutational loads associate with improved survival, and tumors from responding
patients are enriched for mutations in the DNA repair gene BRCA2. Innately
resistant tumors display a transcriptional signature (referred to as the IPRES,
or innate anti-PD-1 resistance), indicating concurrent up-expression of genes
involved in the regulation of mesenchymal transition, cell adhesion,
extracellular matrix remodeling, angiogenesis, and wound healing. Notably,
mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor)
induces similar signatures in melanoma, suggesting that a non-genomic form of
MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy.
Validation of the IPRES in other independent tumor cohorts defines a
transcriptomic subset across distinct types of advanced cancer. These findings
suggest that attenuating the biological processes that underlie IPRES may
improve anti-PD-1 response in melanoma and other cancer types.