Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids.
Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids.
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DOI：
10.1158/2159-8290.cd-17-0833
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发表时间：
2018-03
期刊：
影响因子：
28.2
通讯作者：
Barbie DA
中科院分区：
文献类型：
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作者：
Jenkins RW;Aref AR;Lizotte PH;Ivanova E;Stinson S;Zhou CW;Bowden M;Deng J;Liu H;Miao D;He MX;Walker W;Zhang G;Tian T;Cheng C;Wei Z;Palakurthi S;Bittinger M;Vitzthum H;Kim JW;Merlino A;Quinn M;Venkataramani C;Kaplan JA;Portell A;Gokhale PC;Phillips B;Smart A;Rotem A;Jones RE;Keogh L;Anguiano M;Stapleton L;Jia Z;Barzily-Rokni M;Cañadas I;Thai TC;Hammond MR;Vlahos R;Wang ES;Zhang H;Li S;Hanna GJ;Huang W;Hoang MP;Piris A;Eliane JP;Stemmer-Rachamimov AO;Cameron L;Su MJ;Shah P;Izar B;Thakuria M;LeBoeuf NR;Rabinowits G;Gunda V;Parangi S;Cleary JM;Miller BC;Kitajima S;Thummalapalli R;Miao B;Barbie TU;Sivathanu V;Wong J;Richards WG;Bueno R;Yoon CH;Miret J;Herlyn M;Garraway LA;Van Allen EM;Freeman GJ;Kirschmeier PT;Lorch JH;Ott PA;Hodi FS;Flaherty KT;Kamm RD;Boland GM;Wong KK;Dornan D;Paweletz CP;Barbie DA
结合肿瘤微环境（TME）特征并模拟免疫检查点阻断（ICB）动态反应的离体系统可能有助于精准免疫肿瘤学和有效联合疗法的开发。在这里，我们展示了使用小鼠和患者来源的器官型肿瘤球体 (MDOTS/PDOTS) 询问对 ICB 的离体反应的能力。从小鼠和人类肿瘤中分离的 MDOTS/PDOTS 保留了自体淋巴和骨髓细胞群，并在短期 3 维微流体培养中对 ICB 做出反应。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 的反应和耐药性。 MDOTS 分析表明，TBK1/IKKε 抑制增强了对 PD-1 阻断的反应，从而有效预测了体内肿瘤反应。对 PDOTS 中分泌的细胞因子进行系统分析，捕获了与 PD-1 阻断反应和抵抗相关的关键特征。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。
Ex vivo systems that incorporate features of the tumor microenvironment (TME) 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 3-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.