RT Journal Article
SR Electronic
T1 <em>Ex Vivo</em> Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids
JF Cancer Discovery
JO Cancer Discov
FD American Association for Cancer Research
SP 196
OP 215
DO 10.1158/2159-8290.CD-17-0833
VO 8
IS 2
A1 Jenkins, Russell W.
A1 Aref, Amir R.
A1 Lizotte, Patrick H.
A1 Ivanova, Elena
A1 Stinson, Susanna
A1 Zhou, Chensheng W.
A1 Bowden, Michaela
A1 Deng, Jiehui
A1 Liu, Hongye
A1 Miao, Diana
A1 He, Meng Xiao
A1 Walker, William
A1 Zhang, Gao
A1 Tian, Tian
A1 Cheng, Chaoran
A1 Wei, Zhi
A1 Palakurthi, Sangeetha
A1 Bittinger, Mark
A1 Vitzthum, Hans
A1 Kim, Jong Wook
A1 Merlino, Ashley
A1 Quinn, Max
A1 Venkataramani, Chandrasekar
A1 Kaplan, Joshua A.
A1 Portell, Andrew
A1 Gokhale, Prafulla C.
A1 Phillips, Bart
A1 Smart, Alicia
A1 Rotem, Asaf
A1 Jones, Robert E.
A1 Keogh, Lauren
A1 Anguiano, Maria
A1 Stapleton, Lance
A1 Jia, Zhiheng
A1 Barzily-Rokni, Michal
A1 Cañadas, Israel
A1 Thai, Tran C.
A1 Hammond, Marc R.
A1 Vlahos, Raven
A1 Wang, Eric S.
A1 Zhang, Hua
A1 Li, Shuai
A1 Hanna, Glenn J.
A1 Huang, Wei
A1 Hoang, Mai P.
A1 Piris, Adriano
A1 Eliane, Jean-Pierre
A1 Stemmer-Rachamimov, Anat O.
A1 Cameron, Lisa
A1 Su, Mei-Ju
A1 Shah, Parin
A1 Izar, Benjamin
A1 Thakuria, Manisha
A1 LeBoeuf, Nicole R.
A1 Rabinowits, Guilherme
A1 Gunda, Viswanath
A1 Parangi, Sareh
A1 Cleary, James M.
A1 Miller, Brian C.
A1 Kitajima, Shunsuke
A1 Thummalapalli, Rohit
A1 Miao, Benchun
A1 Barbie, Thanh U.
A1 Sivathanu, Vivek
A1 Wong, Joshua
A1 Richards, William G.
A1 Bueno, Raphael
A1 Yoon, Charles H.
A1 Miret, Juan
A1 Herlyn, Meenhard
A1 Garraway, Levi A.
A1 Van Allen, Eliezer M.
A1 Freeman, Gordon J.
A1 Kirschmeier, Paul T.
A1 Lorch, Jochen H.
A1 Ott, Patrick A.
A1 Hodi, F. Stephen
A1 Flaherty, Keith T.
A1 Kamm, Roger D.
A1 Boland, Genevieve M.
A1 Wong, Kwok-Kin
A1 Dornan, David
A1 Paweletz, Cloud Peter
A1 Barbie, David A.
YR 2018
UL http://cancerdiscovery.aacrjournals.org/content/8/2/196.abstract
AB 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