A Genetic Mouse Model Recapitulates Immune Checkpoint Inhibitors-Associated Myocarditis and Supports a Mechanism-Based Therapeutic Intervention

被引:203
作者
Wei, Spencer C. [1 ]
Meijers, Wouter C. [2 ]
Axelrod, Margaret L. [2 ]
Anang, Nana-Ama A. S. [1 ]
Screever, Elles M. [2 ]
Wescott, Elizabeth C. [3 ]
Johnson, Douglas B. [2 ]
Whitley, Elizabeth [4 ]
Lehmann, Lorenz [5 ,6 ]
Courand, Pierre-Yves [7 ,9 ]
Mancuso, James J. [1 ]
Himmel, Lauren E. [3 ]
Lebrun-Vignes, Benedicte [8 ,10 ]
Wleklinski, Matthew J. [2 ]
Knollmann, Bjorn C. [2 ]
Srinivasan, Jayashree [11 ]
Li, Yu [11 ]
Atolagbe, Oluwatomisin T. [1 ]
Rao, Xiayu [3 ]
Zhao, Yang [12 ]
Wang, Jing [12 ]
Ehrlich, Lauren I. R. [11 ,13 ]
Sharma, Padmanee [14 ,15 ]
Salem, Joe-Elie [2 ,8 ,10 ]
Balko, Justin M. [2 ,3 ]
Moslehi, Javid J. [2 ]
Allison, James P. [1 ,15 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Immunol, Houston, TX USA
[2] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA
[3] Vanderbilt Univ, Dept Pathol Microbiol & Immunol, Med Ctr, Nashville, TN USA
[4] Univ Texas MD Anderson Canc Ctr, Dept Vet Med & Surg, Houston, TX USA
[5] Univ Hosp Heidelberg, Dept Cardiol, Heidelberg, Germany
[6] German Ctr Cardiovasc Res DZHK, German Res Ctr DKFZ, Partner Site Heidelberg Mannheim, Heidelberg, Germany
[7] Hosp Civils Lyon, Hop Croix Rousse, Serv Cardiol, IMMUCARE, Lyon, France
[8] Hop Lyon Sud, Lyon, France
[9] Univ Lyon, CREATIS UMR INSERM U1044, INSA, Lyon, France
[10] Sorbonne Univ, Dept Pharmacol, APHP, INSERM,CIC 1901,UNICO GRECO Cardionncol Program, Paris, France
[11] Univ Texas Austin, Dept Mol Biosci, Austin, TX USA
[12] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX USA
[13] Univ Texas Austin, Liverstrong Canc Inst, Dell Med Sch, Austin, TX USA
[14] Univ Texas MD Anderson Canc Ctr, Dept Genitourinary Med Oncol, Houston, TX USA
[15] Univ Texas MD Anderson Canc Ctr, Parker Inst Canc Immunotherapy, Houston, TX USA
关键词
DILATED CARDIOMYOPATHY; AUTOIMMUNE; IPILIMUMAB; NIVOLUMAB; DATABASE;
D O I
10.1158/2159-8290.CD-20-0856
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have trans- formed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of Ctla4 in the context of complete genetic absence of Pdcd1 leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4-Ig(abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. SIGNIFICANCE: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4-Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies.
引用
收藏
页码:614 / 625
页数:12
相关论文
共 39 条
[1]   QuPath: Open source software for digital pathology image analysis [J].
Bankhead, Peter ;
Loughrey, Maurice B. ;
Fernandez, Jose A. ;
Dombrowski, Yvonne ;
Mcart, Darragh G. ;
Dunne, Philip D. ;
McQuaid, Stephen ;
Gray, Ronan T. ;
Murray, Liam J. ;
Coleman, Helen G. ;
James, Jacqueline A. ;
Salto-Tellez, Manuel ;
Hamilton, Peter W. .
SCIENTIFIC REPORTS, 2017, 7
[2]   Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens A Systematic Review and Meta-analysis [J].
Barroso-Sousa, Romualdo ;
Barry, William T. ;
Garrido-Castro, Ana C. ;
Hodi, F. Stephen ;
Min, Le ;
Krop, Ian E. ;
Tolaney, Sara M. .
JAMA ONCOLOGY, 2018, 4 (02) :173-182
[3]   Mouse Phenome Database: an integrative database and analysis suite for curated empirical phenotype data from laboratory mice [J].
Bogue, Molly A. ;
Grubb, Stephen C. ;
Walton, David O. ;
Philip, Vivek M. ;
Kolishovski, Georgi ;
Stearns, Tim ;
Dunn, Matthew H. ;
Skelly, Daniel A. ;
Kadakkuzha, Beena ;
TeHennepe, Gregg ;
Kunde-Ramamoorthy, Govindarajan ;
Chesler, Elissa J. .
NUCLEIC ACIDS RESEARCH, 2018, 46 (D1) :D843-D850
[4]   Thymocyte development is normal in CTLA-4-deficient mice [J].
Chambers, CA ;
Cado, D ;
Truong, T ;
Allison, JP .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (17) :9296-9301
[5]   Molecular mechanisms of T cell co-stimulation and co-inhibition [J].
Chen, Lieping ;
Flies, Dallas B. .
NATURE REVIEWS IMMUNOLOGY, 2013, 13 (04) :227-242
[6]   Pathogenesis and diagnosis of myocarditis [J].
Elamm, Chantal ;
Fairweather, DeLisa ;
Cooper, Leslie T. .
HEART, 2012, 98 (11) :835-840
[7]   Clinical Features, Management, and Outcomes of Immune Checkpoint Inhibitor-Related Cardiotoxicity [J].
Escudier, Marion ;
Cautela, Jennifer ;
Malissen, Nausicaa ;
Ancedy, Yann ;
Orabona, Morgane ;
Pinto, Johan ;
Monestier, Sandrine ;
Grob, Jean-Jacques ;
Scemama, Ugo ;
Jacquier, Alexis ;
Lalevee, Nathalie ;
Barraud, Jeremie ;
Peyrol, Michael ;
Laine, Marc ;
Bonello, Laurent ;
Paganelli, Franck ;
Cohen, Ariel ;
Barlesi, Fabrice ;
Ederhy, Stephane ;
Thuny, Franck .
CIRCULATION, 2017, 136 (21) :2085-2087
[8]   Fulminant Myocarditis with Combination Immune Checkpoint Blockade [J].
Johnson, Douglas B. dbj ;
Balko, Justin M. jmb ;
Compton, Margaret L. mlc ;
Chalkias, Spyridon sc ;
Gorham, Joshua jc ;
Xu, Yaomin yx ;
Hicks, Mellissa mh ;
Puzanov, Igor ip ;
Alexander, Matthew R. mra ;
Bloomer, Tyler L. tlb ;
Becker, Jason R. jrb ;
Slosky, David A. das ;
Phillips, Elizabeth J. ejp ;
Pilkinton, Mark A. map ;
Craig-Owens, Laura lco ;
Kola, Nina nk ;
Plautz, Gregory gp ;
Reshef, Daniel S. dsr ;
Deutsch, Jonathan S. jsd ;
Deering, Raquel P. rpd ;
Olenchock, Benjamin A. bao ;
Lichtman, Andrew H. ahl ;
Roden, Dan M. dmr ;
Seidman, Christine E. ces ;
Koralnik, Igor J. ijk ;
Seidman, Jonathan G. jgs ;
Hoffman, Robert D. rdh ;
Taube, Janis M. jmt ;
Diaz, Luis A. Jr lad ;
Anders, Robert A. raa ;
Sosman, Jeffrey A. jas ;
Moslehi, Javid J. jjm .
NEW ENGLAND JOURNAL OF MEDICINE, 2016, 375 (18) :1749-1755
[9]   T cell costimulation blockade blunts pressure overload-induced heart failure [J].
Kallikourdis, Marinos ;
Martini, Elisa ;
Carullo, Pierluigi ;
Sardi, Claudia ;
Roselli, Giuliana ;
Greco, Carolina M. ;
Vignali, Debora ;
Riva, Federica ;
Berre, Anne Marie Ormbostad ;
Stolen, Tomas O. ;
Fumero, Andrea ;
Faggian, Giuseppe ;
Di Pasquale, Elisa ;
Elia, Leonardo ;
Rumio, Cristiano ;
Catalucci, Daniele ;
Papait, Roberto ;
Condorelli, Gianluigi .
NATURE COMMUNICATIONS, 2017, 8
[10]   Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent [J].
Kamphorst, Alice O. ;
Wieland, Andreas ;
Nasti, Tahseen ;
Yang, Shu ;
Zhang, Ruan ;
Barber, Daniel L. ;
Konieczny, Bogumila T. ;
Daugherty, Candace Z. ;
Koenig, Lydia ;
Yu, Ke ;
Sica, Gabriel L. ;
Sharpe, Arlene H. ;
Freeman, Gordon J. ;
Blazar, Bruce R. ;
Turka, Laurence A. ;
Owonikoko, Taofeek K. ;
Pillai, Rathi N. ;
Ramalingam, Suresh S. ;
Araki, Koichi ;
Ahmed, Rafi .
SCIENCE, 2017, 355 (6332) :1423-1427