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

Abstract
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. 143.
See related article by Deng et al., p. 216.
This article is highlighted in the In This Issue feature, p. 127