Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids

被引：433

作者：

Jenkins, Russell W. ^{[1
,2
]}

Aref, Amir R. ^{[1
,3
]}

Lizotte, Patrick H. ^{[1
,3
]}

Ivanova, Elena ^{[1
,3
]}

Stinson, Susanna ^{[4
]}

Zhou, Chensheng W. ^{[1
,5
]}

Bowden, Michaela ^{[1
,5
]}

Deng, Jiehui ^{[1
]}

Liu, Hongye ^{[1
,3
,6
]}

Miao, Diana ^{[1
,7
,8
]}

He, Meng Xiao ^{[1
,7
,8
,9
]}

Walker, William ^{[1
,3
]}

Zhang, Gao ^{[10
,11
]}

Tian, Tian ^{[12
]}

Cheng, Chaoran ^{[12
]}

Wei, Zhi ^{[12
]}

Palakurthi, Sangeetha ^{[1
,3
]}

Bittinger, Mark ^{[1
,3
]}

Vitzthum, Hans ^{[2
]}

Kim, Jong Wook ^{[1
,7
,8
]}

Merlino, Ashley ^{[1
]}

Quinn, Max ^{[1
]}

Venkataramani, Chandrasekar ^{[4
]}

Kaplan, Joshua A. ^{[4
]}

Portell, Andrew ^{[1
,3
]}

Gokhale, Prafulla C. ^{[1
,3
]}

Phillips, Bart ^{[4
]}

Smart, Alicia ^{[1
,7
,8
]}

Rotem, Asaf ^{[1
]}

Jones, Robert E. ^{[1
,3
]}

Keogh, Lauren ^{[1
,3
]}

Anguiano, Maria ^{[13
]}

Stapleton, Lance ^{[4
]}

Jia, Zhiheng ^{[4
]}

Barzily-Rokni, Michal ^{[2
]}

Canadas, Israel ^{[1
]}

Thai, Tran C. ^{[1
]}

Hammond, Marc R. ^{[2
]}

Vlahos, Raven ^{[1
,5
]}

Wang, Eric S. ^{[14
]}

Zhang, Hua ^{[1
]}

Li, Shuai ^{[1
]}

Hanna, Glenn J. ^{[1
]}

Huang, Wei ^{[1
,3
]}

Hoang, Mai P. ^{[15
]}

Piris, Adriano ^{[16
,17
]}

Eliane, Jean-Pierre ^{[15
]}

Stemmer-Rachamimov, Anat O. ^{[15
]}

Cameron, Lisa ^{[18
]}

Su, Mei-Ju ^{[1
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[2] Harvard Med Sch, Massachusetts Gen Hosp, Canc Ctr, Div Med Oncol, Boston, MA USA

[3] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02115 USA

[4] Gilead Sci, Foster City, CA USA

[5] Dana Farber Canc Inst, Ctr Mol Oncol Pathol, Boston, MA 02115 USA

[6] Harvard Med Sch, Lab Syst Pharmacol, Boston, MA USA

[7] Broad Inst Harvard, Cambridge, MA USA

[8] MIT, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[9] Harvard Grad Program Biophys, Boston, MA USA

[10] Wistar Inst Anat & Biol, Melanoma Res Ctr, 3601 Spruce St, Philadelphia, PA 19104 USA

[11] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA

[12] New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA

[13] Univ Navarra, Ctr Appl Med Res, Pamplona, Spain

[14] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[15] Harvard Med Sch, Massachusetts Gen Hosp, Dept Pathol, Boston, MA USA

[16] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[17] Harvard Med Sch, Boston, MA USA

[18] Dana Farber Canc Inst, Confocal & Light Microscopy Core Facil, Boston, MA 02115 USA

[19] Harvard Med Sch, Brigham & Womens Hosp, Dept Dermatol, Boston, MA USA

[20] Harvard Med Sch, Massachusetts Gen Hosp, Dept Surg, Boston, MA USA

[21] Harvard Med Sch, Brigham & Womens Hosp, Dept Surg Oncol, Boston, MA USA

[22] MIT, Dept Mech Engn, Cambridge, MA 02139 USA

[23] Harvard Med Sch, Brigham & Womens Hosp, Div Thorac Surg, Boston, MA USA

[24] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

CANCER DISCOVERY | 2018年 / 8卷 / 02期

关键词：

IMMUNE-CHECKPOINT BLOCKADE; REGULATORY T; KINASE TBK1; CANCER; RESISTANCE; CELLS; CTLA-4; MELANOMA; IMMUNOTHERAPY; PEMBROLIZUMAB;

D O I：

10.1158/2159-8290.CD-17-0833

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts. (C) 2017 AACR.

引用

页码：196 / 215

页数：20

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