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Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids.
Cancer Discovery ( IF 28.2 ) Pub Date : 2017-11-03 , DOI: 10.1158/2159-8290.cd-17-0833
Russell W Jenkins 1, 2 , Amir R Aref 1, 3 , Patrick H Lizotte 1, 3 , Elena Ivanova 1, 3 , Susanna Stinson 4 , Chensheng W Zhou 1, 5 , Michaela Bowden 1, 5 , Jiehui Deng 1 , Hongye Liu 1, 3, 6 , Diana Miao 1, 7 , Meng Xiao He 1, 7, 8 , William Walker 1, 3 , Gao Zhang 9 , Tian Tian 10 , Chaoran Cheng 10 , Zhi Wei 10 , Sangeetha Palakurthi 1, 3 , Mark Bittinger 1, 3 , Hans Vitzthum 2 , Jong Wook Kim 1, 7 , Ashley Merlino 1 , Max Quinn 1 , Chandrasekar Venkataramani 4 , Joshua A Kaplan 4 , Andrew Portell 1, 3 , Prafulla C Gokhale 1, 3 , Bart Phillips 4 , Alicia Smart 1, 7 , Asaf Rotem 1 , Robert E Jones 1, 3 , Lauren Keogh 1, 3 , Maria Anguiano 11 , Lance Stapleton 4 , Zhiheng Jia 4 , Michal Barzily-Rokni 2 , Israel Cañadas 1 , Tran C Thai 1 , Marc R Hammond 2 , Raven Vlahos 1, 5 , Eric S Wang 12 , Hua Zhang 1 , Shuai Li 1 , Glenn J Hanna 1 , Wei Huang 1, 3 , Mai P Hoang 13 , Adriano Piris 14 , Jean-Pierre Eliane 13 , Anat O Stemmer-Rachamimov 13 , Lisa Cameron 15 , Mei-Ju Su 1 , Parin Shah 1 , Benjamin Izar 1, 7 , Manisha Thakuria 1, 16 , Nicole R LeBoeuf 1, 16 , Guilherme Rabinowits 1 , Viswanath Gunda 17 , Sareh Parangi 17 , James M Cleary 1 , Brian C Miller 1 , Shunsuke Kitajima 1 , Rohit Thummalapalli 1 , Benchun Miao 2 , Thanh U Barbie 18 , Vivek Sivathanu 19 , Joshua Wong 1 , William G Richards 20 , Raphael Bueno 20 , Charles H Yoon 18 , Juan Miret 1, 3 , Meenhard Herlyn 9 , Levi A Garraway 1 , Eliezer M Van Allen 1, 7 , Gordon J Freeman 1 , Paul T Kirschmeier 1, 3 , Jochen H Lorch 1 , Patrick A Ott 1 , F Stephen Hodi 1 , Keith T Flaherty 2 , Roger D Kamm 19, 21 , Genevieve M Boland 17 , Kwok-Kin Wong 1, 3 , David Dornan 4 , Cloud Peter Paweletz 1, 3 , David A Barbie 1
Affiliation  

Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens.Significance: Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of ex vivo profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts. Cancer Discov; 8(2); 196-215. ©2017 AACR.See related commentary by Balko and Sosman, p. 143See related article by Deng et al., p. 216This article is highlighted in the In This Issue feature, p. 127.

中文翻译:

使用器官型肿瘤球体对 PD-1 阻断剂进行体外分析。

结合肿瘤微环境特征并模拟对免疫检查点阻断 (ICB) 的动态反应的体外系统可能有助于精准免疫肿瘤学和开发有效的联合疗法。在这里,我们展示了使用小鼠和患者衍生的器官型肿瘤球体 (MDOTS/PDOTS) 来询问对 ICB 的离体反应的能力。从小鼠和人类肿瘤中分离出来的 MDOTS/PDOTS 保留了自体淋巴和骨髓细胞群,并在短期 3D 微流体培养中对 ICB 有反应。使用源自已建立的免疫活性小鼠肿瘤模型的 MDOTS 概括了对 ICB 的反应和抗性。MDOTS 分析表明 TBK1/IKKε 抑制增强了对 PD-1 阻断的反应,有效预测体内肿瘤反应 PDOTS 中分泌细胞因子的系统分析捕获了与对 PD-1 阻断的反应和抗性相关的关键特征。因此,MDOTS/PDOTS 分析代表了一个使用已建立的小鼠模型以及临床相关患者标本评估 ICB 的新平台。意义:对许多患者来说,对 PD-1 阻断的耐药性仍然是一个挑战,并且缺乏指导治疗的生物标志物。在这里,我们证明了 PD-1 阻断的离体分析以询问肿瘤免疫微环境、开发治疗组合并促进精准免疫肿瘤学工作的可行性。癌症发现;8(2);196-215。©2017 AACR。参见 Balko 和 Sosman 的相关评论,p。143 见 Deng 等人的相关文章,第 216这篇文章在 In This Issue 功能中突出显示,页。127.
更新日期:2018-02-05
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