Ex vivo profiling of PD-1 blockade using organotypic tumor spheroids

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

Research output: Contribution to journalArticlepeer-review

138 Scopus citations

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/ IKKe 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 profi ling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts.

Original languageEnglish (US)
Pages (from-to)196-215
Number of pages20
JournalCancer Discovery
Volume8
Issue number2
DOIs
StatePublished - Feb 2018

All Science Journal Classification (ASJC) codes

  • Oncology

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