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 language | English (US) |
|---|---|
| Pages (from-to) | 196-215 |
| Number of pages | 20 |
| Journal | Cancer Discovery |
| Volume | 8 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2018 |
All Science Journal Classification (ASJC) codes
- Oncology
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In: Cancer Discovery, Vol. 8, No. 2, 02.2018, p. 196-215.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Ex vivo profiling of PD-1 blockade using organotypic tumor spheroids
AU - Jenkins, Russell W.
AU - Aref, Amir R.
AU - Lizotte, Patrick H.
AU - Ivanova, Elena
AU - Stinson, Susanna
AU - Zhou, Chensheng W.
AU - Bowden, Michaela
AU - Deng, Jiehui
AU - Liu, Hongye
AU - Miao, Diana
AU - He, Meng Xiao
AU - Walker, William
AU - Zhang, Gao
AU - Tian, Tian
AU - Cheng, Chaoran
AU - Wei, Zhi
AU - Palakurthi, Sangeetha
AU - Bittinger, Mark
AU - Vitzthum, Hans
AU - Kim, Jong Wook
AU - Merlino, Ashley
AU - Quinn, Max
AU - Venkataramani, Chandrasekar
AU - Kaplan, Joshua A.
AU - Portell, Andrew
AU - Gokhale, Prafulla C.
AU - Phillips, Bart
AU - Smart, Alicia
AU - Rotem, Asaf
AU - Jones, Robert E.
AU - Keogh, Lauren
AU - Anguiano, Maria
AU - Stapleton, Lance
AU - Jia, Zhiheng
AU - Barzily-Rokni, Michal
AU - Cañadas, Israel
AU - Thai, Tran C.
AU - Hammond, Marc R.
AU - Vlahos, Raven
AU - Wang, Eric S.
AU - Zhang, Hua
AU - Li, Shuai
AU - Hanna, Glenn J.
AU - Huang, Wei
AU - Hoang, Mai P.
AU - Piris, Adriano
AU - Eliane, Jean Pierre
AU - Stemmer-Rachamimov, Anat O.
AU - Cameron, Lisa
AU - Su, Mei Ju
AU - Shah, Parin
AU - Izar, Benjamin
AU - Thakuria, Manisha
AU - LeBoeuf, Nicole R.
AU - Rabinowits, Guilherme
AU - Gunda, Viswanath
AU - Parangi, Sareh
AU - Cleary, James M.
AU - Miller, Brian C.
AU - Kitajima, Shunsuke
AU - Thummalapalli, Rohit
AU - Miao, Benchun
AU - Barbie, Thanh U.
AU - Sivathanu, Vivek
AU - Wong, Joshua
AU - Richards, William G.
AU - Bueno, Raphael
AU - Yoon, Charles H.
AU - Miret, Juan
AU - Herlyn, Meenhard
AU - Garraway, Levi A.
AU - Van Allen, Eliezer M.
AU - Freeman, Gordon J.
AU - Kirschmeier, Paul T.
AU - Lorch, Jochen H.
AU - Ott, Patrick A.
AU - Stephen Hodi, F.
AU - Flaherty, Keith T.
AU - Kamm, Roger D.
AU - Boland, Genevieve M.
AU - Wong, Kwok Kin
AU - Dornan, David
AU - Paweletz, Cloud Peter
AU - Barbie, David A.
N1 - Funding Information: We thank the patients for the use of clinical specimens without which this study would not have been possible. We also thank the clinical and support staff at Massachusetts General Hospital, Brigham and Women’s Hospital, and the Dana-Farber Cancer Institute for their assistance in these efforts. In particular, we thank the clinical research coordinators who were instrumental in procuring and transporting clinical specimens, especially Michael Manos, Phillip Groden, Sarah Garcia, and Shauna Blackmon. We thank Mei Zhang from the Pathology Department at Brigham and Women’s Hospital for immunohistochemical staining. Financial support was provided by the Robert A. and Renée E. Belfer Foundation, NCI Training Grant T32CA009172-41 (R.W. Jenkins), the John R. Svenson Fellowship (R.W. Jenkins), NCIR01 CA190394-01 (D.A. Barbie), the Gloria T. Maheu and Heerwagen Family Funds for Lung Cancer Research (D.A. Barbie), the Rising Tide Foundation (D.A. Barbie), and the Expect Miracles Foundation (C.P. Paweletz). Financial support was also provided by NIGMS T32 GM008313 (M.X. He), NSF GRFP DGE1144152 (M.X. He), the Caja Navarra Foundation, the Excellence Doctoral Mobility Grant (M. Anguiano), the Association of Friends of the University of Navarra, the Doctoral Mobility Grant (M. Anguiano), NIH/NCI P01CA120964 (K.-K. Wong), 5R01CA163896-04 (K.-K. Wong), 5R01CA140594-07 (K.-K. Wong), 5R01CA122794-10 (K.-K. Wong), 5R01CA166480-04 (K.-K. Wong), the Gross-Loh Family Fund for Lung Cancer Research (K.-K. Wong), the Susan Spooner Family Lung Cancer Research Fund at Dana-Farber Cancer Institute (K.-K. Wong), 1R01CA149738-01 (S. Parangi), and the Elizabeth and Michael Ruane Fund (S. Parangi). Additional funding was provided by NIH grants P01 CA114046, P01 CA025874, P30 CA010815, and R01 CA047159 and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Melanoma Research Foundation. The support for Shared Resources used in this study was provided by Cancer Center Support Grant (CCSG) CA010815 (to The Wistar Institute). Additional support was provided by a Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT1715). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. Funding Information: We thank the patients for the use of clinical specimens without which this study would not have been possible. We also thank the clinical and support staff at Massachusetts General Hospital, Brigham and Women?s Hospital, and the Dana-Farber Cancer Institute for their assistance in these efforts. In particular, we thank the clinical research coordinators who were instrumental in procuring and transporting clinical specimens, especially Michael Manos, Phillip Groden, Sarah Garcia, and Shauna Blackmon. We thank Mei Zhang from the Pathology Department at Brigham and Women?s Hospital for immunohistochemical staining. Financial support was provided by the Robert A. and Ren?e E. Belfer Foundation, NCI Training Grant T32CA009172-41 (R.W. Jenkins), the John R. Svenson Fellowship (R.W. Jenkins), NCIR01 CA190394-01 (D.A. Barbie), the Gloria T. Maheu and Heerwagen Family Funds for Lung Cancer Research (D.A. Barbie), the Rising Tide Foundation (D.A. Barbie), and the Expect Miracles Foundation (C.P. Paweletz). Financial support was also provided by NIGMS T32 GM008313 (M.X. He), NSF GRFP DGE1144152 (M.X. He), the Caja Navarra Foundation, the Excellence Doctoral Mobility Grant (M. Anguiano), the Association of Friends of the University of Navarra, the Doctoral Mobility Grant (M. Anguiano), NIH/NCI P01CA120964 (K.-K. Wong), 5R01CA163896-04 (K.-K. Wong), 5R01CA140594-07 (K.-K. Wong), 5R01CA122794-10 (K.-K. Wong), 5R01CA166480-04 (K.-K. Wong), the Gross-Loh Family Fund for Lung Cancer Research (K.-K. Wong), the Susan Spooner Family Lung Cancer Research Fund at Dana-Farber Cancer Institute (K.-K. Wong), 1R01CA149738-01 (S. Parangi), and the Elizabeth and Michael Ruane Fund (S. Parangi). Additional funding was provided by NIH grants P01 CA114046, P01 CA025874, P30 CA010815, and R01 CA047159 and by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the Melanoma Research Foundation. The support for Shared Resources used in this study was provided by Cancer Center Support Grant (CCSG) CA010815 (to The Wistar Institute). Additional support was provided by a Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT1715). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. Publisher Copyright: © 2017 American Association for Cancer Research.
PY - 2018/2
Y1 - 2018/2
N2 - 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.
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/ 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.
UR - http://www.scopus.com/inward/record.url?scp=85041418590&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041418590&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-17-0833
DO - 10.1158/2159-8290.CD-17-0833
M3 - Article
C2 - 29101162
AN - SCOPUS:85041418590
SN - 2159-8274
VL - 8
SP - 196
EP - 215
JO - Cancer Discovery
JF - Cancer Discovery
IS - 2
ER -