PD-1 blockade induces responses by inhibiting adaptive immune resistance.
PD-1 blockade induces responses by inhibiting adaptive immune resistance.
复制标题
DOI：
10.1038/nature13954
复制
发表时间：
2014-11-27
期刊：
影响因子：
64.8
通讯作者：
Ribas, Antoni
中科院分区：
文献类型：
--
作者：
Tumeh, Paul C.;Harview, Christina L.;Yearley, Jennifer H.;Shintaku, I. Peter;Taylor, Emma J. M.;Robert, Lidia;Chmielowski, Bartosz;Spasic, Marko;Henry, Gina;Ciobanu, Voicu;West, Alisha N.;Carmona, Manuel;Kivork, Christine;Seja, Elizabeth;Cherry, Grace;Gutierrez, Antonio J.;Grogan, Tristan R.;Mateus, Christine;Tomasic, Gorana;Glaspy, John A.;Emerson, Ryan O.;Robins, Harlan;Pierce, Robert H.;Elashoff, David A.;Robert, Caroline;Ribas, Antoni
靶向程序性死亡-1（PD-1）受体的治疗在各种癌症患者中显示出前所未有的持久临床反应率。癌症组织限制宿主免疫应答的一种机制是通过上调PD-1配体（PD-L1）及其与抗原特异性CD 8 T细胞上的PD-1的连接（称为适应性免疫抗性）。在这里，我们表明，预先存在的CD 8 T细胞明显位于浸润性肿瘤边缘与PD-1/PD-L1免疫抑制轴的表达相关，并可能预测对治疗的反应。我们使用定量免疫组织化学、定量多重免疫荧光和下一代T细胞受体（TCR）测序分析了46例转移性黑色素瘤患者在抗PD 1治疗（pembrolizumab）之前和期间获得的样本。在连续取样的肿瘤中，有反应的患者显示肿瘤内CD 8 + T细胞的增殖与肿瘤大小的放射学缩小直接相关。从应答患者获得的治疗前样本显示，在侵袭性肿瘤边缘和肿瘤内部，表达CD 8、PD 1和PD-L1的细胞数量较高，PD-1和PD-L1之间非常接近，并且TCR库更具克隆性。使用多变量分析，我们建立了一个基于浸润边缘CD 8表达的预测模型，并在15例患者的独立队列中验证了该模型。我们的研究结果表明，治疗性PD-1阻断后的肿瘤消退需要预先存在的CD 8 + T细胞，这些细胞受到PD-1/PD-L1介导的适应性免疫抵抗的负调控。
Therapies that target the programmed death-1 (PD-1) receptor have shown unprecedented rates of durable clinical responses in patients with various cancer types. 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). 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 analyzed samples from 46 patients with metastatic melanoma obtained before and during anti-PD1 therapy (pembrolizumab) using quantitative immunohistochemistry, quantitative multiplex immunofluorescence, and next generation sequencing for T-cell receptors (TCR). In serially sampled tumours, responding patients showed proliferation of intratumoural CD8+ T-cells that directly correlated with radiographic reduction in tumour size. Pre-treatment samples obtained from responding patients showed higher numbers of CD8, PD1, 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 following therapeutic PD-1 blockade requires pre-existing CD8+ T cells that are negatively regulated by PD-1/PD-L1 mediated adaptive immune resistance.
登录
查看更多内容
DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
PD-1，PD-1配体的关联以及肿瘤免疫微环境的其他特征与抗PD-1治疗的响应。
DOI：
10.1158/1078-0432.ccr-13-3271
发表时间：
2014-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Taube JM;Klein A;Brahmer JR;Xu H;Pan X;Kim JH;Chen L;Pardoll DM;Topalian SL;Anders RA
通讯作者：
Anders RA
黑色素瘤肿瘤微环境中PD-L1，IDO和T（REGS）的上调由CD8（+）T细胞驱动。
影响因子：
17.1
作者：
Spranger S;Spaapen RM;Zha Y;Williams J;Meng Y;Ha TT;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1056/nejmoa1200694
发表时间：
2012-06-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Brahmer JR;Tykodi SS;Chow LQ;Hwu WJ;Topalian SL;Hwu P;Drake CG;Camacho LH;Kauh J;Odunsi K;Pitot HC;Hamid O;Bhatia S;Martins R;Eaton K;Chen S;Salay TM;Alaparthy S;Grosso JF;Korman AJ;Parker SM;Agrawal S;Goldberg SM;Pardoll DM;Gupta A;Wigginton JM
通讯作者：
Wigginton JM
影响因子：
82.9
作者：
Parsa, Andrew T.;Waldron, James S.;Pieper, Russell O.
通讯作者：
Pieper, Russell O.