Nature：新方法可预测新药对黑素瘤患者效果

  近日，发表于国际杂志Nature上的一篇研究论文中，来自加州大学洛杉矶分校的研究人员开发了一种新型的方法学，其可以帮助预测为何某些恶性黑色素瘤患者对药物pembrolizumab有反应，而有些患者却没有一点反应。

  研究者Antoni Ribas表示，我们是最先研究pembrolizumab药物的，该药物是今年9月份被FDA批准的一种用于治疗黑色素瘤和其它癌症的新药。一种名为PD-1的蛋白可以抑制免疫系统中T细胞攻击癌细胞，而药物pembrolizumab则可以解除PD-1对T细胞的抑制作用，从而使得免疫系统恢复杀灭癌细胞的功能。

  Tumeh表示，我们利用pembrolizumab在治疗黑色素瘤患者上获得了非常好的临床治疗效果，但目前该药物仅对30%的患者有效，本文研究中我们开发了一种新型技术，其可以帮助选择那些更易于对该药物疗法产生反应的患者。研究者的目的就是揭示为何某些患者容易对疗法产生反应而有些患者却丝毫反应都没有。

  如今经过了两年研究，研究人员对46名患者分别在肿瘤组织活检前和疗法期间进行了分析研究，分析了患者的活检组织并且根据患者对药物pembrolizumab是否产生反应来对这些组织进行分类，最终研究人员利用分析结果成功开发了一种可以预测患者对药物疗法是否起反应的新型方法学。

  下一步，研究人员将对那些对药物pembrolizumab无反应的不同类别患者进行分类，以便可以调整针对不同患者机体肿瘤的治疗措施。（转化医学网360zhyx.com）

  本文系转化医学网原创翻译整理，欢迎转载！转载请注明来源并附原文链接。谢谢！
转化医学网推荐的原文摘要：

PD-1 blockade induces responses by inhibiting adaptive immune resistance
Nature doi:10.1038/nature13954
Paul C. Tumeh, Christina L. Harview, Jennifer H. Yearley, I. Peter Shintaku, Emma J. M. Taylor, Lidia Robert, Bartosz Chmielowski, Marko Spasic, Gina Henry, Voicu Ciobanu, Alisha N. West, Manuel Carmona, Christine Kivork, Elizabeth Seja, Grace Cherry, Antonio J. Gutierrez, Tristan R. Grogan, Christine Mateus, Gorana Tomasic, John A. Glaspy, Ryan O. Emerson, Harlan Robins, Robert H. Pierce, David A. Elashoff, Caroline Robert et al.
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types1, 2, 3, 4, 5. One mechanism by which cancer tissues limit the host immune response is via upregulation of PD-1 ligand (PD-L1) and its ligation to PD-1 on antigen-specific CD8+ T cells (termed adaptive immune resistance)6, 7. Here we show that pre-existing CD8+ T cells distinctly located at the invasive tumour margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to therapy. We analysed samples from 46 patients with metastatic melanoma obtained before and during anti-PD-1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next-generation sequencing for T-cell antigen receptors (TCRs). In serially sampled tumours, patients responding to treatment showed proliferation of intratumoral CD8+ T cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8-, PD-1- and PD-L1-expressing cells at the invasive tumour margin and inside tumours, with close proximity between PD-1 and PD-L1, and a more clonal TCR repertoire. Using multivariate analysis, we established a predictive model based on CD8 expression at the invasive margin and validated the model in an independent cohort of 15 patients. Our findings indicate that tumour regression after therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance.