Thymus alterations and susceptibility to immune checkpoint inhibitor myocarditis
Charlotte Fenioux
(1, 2)
,
Baptiste Abbar
(3, 1)
,
Samia Boussouar
(2)
,
Marie Bretagne
(4)
,
John Power
(5)
,
Javid Moslehi
(6)
,
Paul Gougis
(7, 8)
,
Damien Amelin
(9, 10)
,
Agnès Dechartres
(11, 2)
,
Lorenz Lehmann
(12, 13)
,
Pierre-Yves Courand
(14)
,
Jennifer Cautela
(15)
,
Joachim Alexandre
(16, 17)
,
Adrien Procureur
(2)
,
Antoine Rozes
(2, 4)
,
Sarah Leonard-Louis
(9, 2)
,
Juan Qin
(18)
,
Nausheen Akhter
,
Nazanin Aghel
,
Kingsley Amidi
,
Elizabeth Anderson
,
Dimitri Arangalage
,
Mandar Aras
,
Aarti Asnani
,
Lauren Baldassarre
,
Rocio Barovila
,
Ana Sofia Barroso
,
Wendy Bottinor
,
Anissa Bouali
,
Eve Cariou
,
Wei-Ting Chang
,
Richard Cheng
,
Shanthini Crusz
,
Anita Deswal
,
Pierre-Yves Dietrich
,
Grace Dy
,
Clemence Docq
,
Steven Ewer
,
Suran Fernando
,
Danette Flint
,
Roberta Florido
,
Satoshi Fukushima
,
Elena Galli
,
Elizabeth Gaughan
,
Manhal Habib
,
Andrew Haydon
,
Lucie Heinzerling
,
Osnat Itzhaki Ben Zadok
,
Nahema Issa
,
Anja Karlstaedt
,
Kazuo Kitagawa
,
Michael Layoun
,
Michal Laufer-Perl
,
Carrie Lenneman
,
Darryl Leong
,
Chloe Lesiuk
,
Joshua Levenson
,
Teresa López-Fernández
,
Yan Liu
,
Kristen Machado
,
Pedro Moliner
,
Ryota Morimoto
,
Michel Obeid
,
Anna Narezkina
,
Nicolas Palaskas
,
Giovanni Peretto
,
Nicolas Piriou
,
Juan Carlos Plana
,
Peter Rainer
,
Maxime Robert-Halabi
,
Fanny Rocher
,
Eugenia Rota
,
Francois Roubille
,
Theresa Ruf
,
Shahneen Sandhu
,
Francis Sanjeev
,
Nobuhiko Seki
,
Kazuko Tajiri
,
Yuichi Tamura
,
Franck Thuny
,
Romain Tresorier
,
Isik Turker
,
Ellen Warner
,
Vlad Zaha
,
Han Zhu
,
Rémi Cheynier
(19)
,
Benedicte Charmeteau-de Muylder
(19)
,
Alban Redheuil
(2)
,
Florence Tubach
(20)
,
Jacques Cadranel
,
Audrey Milon
,
Stéphane Ederhy
,
Thomas Similowski
,
Douglas Johnson
,
Ian Pizzo
,
Toniemarie Catalan
,
Olivier Benveniste
(9, 2)
,
Salim Hayek
,
Yves Allenbach
,
Michelle Rosenzwajg
,
Charles Dolladille
,
Joe-Elie Salem
1
Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
2 CHU Pitié-Salpêtrière [AP-HP]
3 CIMI - Centre d'Immunologie et des Maladies Infectieuses
4 CIC Paris-Est - Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière]
5 University of Bath [Bath]
6 UC San Francisco - University of California [San Francisco]
7 RT2Lab - Residual Tumor & Response to Treatment Laboratory [Paris]
8 U932 - Immunité et cancer
9 Centre de recherche en Myologie – U974 SU-INSERM
10 Institut de Myologie
11 iPLESP - Institut Pierre Louis d'Epidémiologie et de Santé Publique
12 Universität Heidelberg [Heidelberg] = Heidelberg University
13 DZHK - German Center for Cardiovascular Research
14 UCBL - Université Claude Bernard Lyon 1
15 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
16 UNICAEN Santé - Université de Caen Normandie - UFR Santé
17 INSERM U1086
18 UC - University of California
19 UPCité - Université Paris Cité
20 SU - Sorbonne Université
2 CHU Pitié-Salpêtrière [AP-HP]
3 CIMI - Centre d'Immunologie et des Maladies Infectieuses
4 CIC Paris-Est - Centre d'investigation clinique Paris Est [CHU Pitié Salpêtrière]
5 University of Bath [Bath]
6 UC San Francisco - University of California [San Francisco]
7 RT2Lab - Residual Tumor & Response to Treatment Laboratory [Paris]
8 U932 - Immunité et cancer
9 Centre de recherche en Myologie – U974 SU-INSERM
10 Institut de Myologie
11 iPLESP - Institut Pierre Louis d'Epidémiologie et de Santé Publique
12 Universität Heidelberg [Heidelberg] = Heidelberg University
13 DZHK - German Center for Cardiovascular Research
14 UCBL - Université Claude Bernard Lyon 1
15 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
16 UNICAEN Santé - Université de Caen Normandie - UFR Santé
17 INSERM U1086
18 UC - University of California
19 UPCité - Université Paris Cité
20 SU - Sorbonne Université
Baptiste Abbar
- Function : Author
- PersonId : 806422
- ORCID : 0000-0002-5907-8131
Pierre-Yves Courand
- Function : Author
- PersonId : 744032
- IdHAL : pierre-yves-courand
- ORCID : 0000-0003-3199-7977
- IdRef : 137452217
Jennifer Cautela
- Function : Author
- PersonId : 775040
- ORCID : 0000-0003-1284-8191
- IdRef : 174909934
Adrien Procureur
- Function : Author
- PersonId : 1341004
- ORCID : 0000-0003-3486-5208
Nausheen Akhter
- Function : Author
Nazanin Aghel
- Function : Author
Kingsley Amidi
- Function : Author
Elizabeth Anderson
- Function : Author
Dimitri Arangalage
- Function : Author
Mandar Aras
- Function : Author
Aarti Asnani
- Function : Author
Lauren Baldassarre
- Function : Author
Rocio Barovila
- Function : Author
Ana Sofia Barroso
- Function : Author
Wendy Bottinor
- Function : Author
Anissa Bouali
- Function : Author
Eve Cariou
- Function : Author
Wei-Ting Chang
- Function : Author
Richard Cheng
- Function : Author
Shanthini Crusz
- Function : Author
Anita Deswal
- Function : Author
Pierre-Yves Dietrich
- Function : Author
Grace Dy
- Function : Author
Clemence Docq
- Function : Author
Steven Ewer
- Function : Author
Suran Fernando
- Function : Author
Danette Flint
- Function : Author
Roberta Florido
- Function : Author
Satoshi Fukushima
- Function : Author
Elena Galli
- Function : Author
Elizabeth Gaughan
- Function : Author
Manhal Habib
- Function : Author
Andrew Haydon
- Function : Author
Lucie Heinzerling
- Function : Author
Osnat Itzhaki Ben Zadok
- Function : Author
Nahema Issa
- Function : Author
Anja Karlstaedt
- Function : Author
Kazuo Kitagawa
- Function : Author
Michael Layoun
- Function : Author
Michal Laufer-Perl
- Function : Author
Carrie Lenneman
- Function : Author
Darryl Leong
- Function : Author
Chloe Lesiuk
- Function : Author
Joshua Levenson
- Function : Author
Teresa López-Fernández
- Function : Author
Yan Liu
- Function : Author
Kristen Machado
- Function : Author
Pedro Moliner
- Function : Author
Ryota Morimoto
- Function : Author
Michel Obeid
- Function : Author
Anna Narezkina
- Function : Author
Nicolas Palaskas
- Function : Author
Giovanni Peretto
- Function : Author
Nicolas Piriou
- Function : Author
Juan Carlos Plana
- Function : Author
Peter Rainer
- Function : Author
Maxime Robert-Halabi
- Function : Author
Fanny Rocher
- Function : Author
Eugenia Rota
- Function : Author
Francois Roubille
- Function : Author
Theresa Ruf
- Function : Author
Shahneen Sandhu
- Function : Author
Francis Sanjeev
- Function : Author
Nobuhiko Seki
- Function : Author
Kazuko Tajiri
- Function : Author
Yuichi Tamura
- Function : Author
Franck Thuny
- Function : Author
Romain Tresorier
- Function : Author
Isik Turker
- Function : Author
Ellen Warner
- Function : Author
Vlad Zaha
- Function : Author
Han Zhu
- Function : Author
Rémi Cheynier
- Function : Author
- PersonId : 1321707
- ORCID : 0000-0003-1146-660X
Alban Redheuil
- Function : Author
- PersonId : 1151215
- ORCID : 0000-0002-1002-9902
- IdRef : 084116234
Florence Tubach
- Function : Author
- PersonId : 1101022
- IdHAL : florencetubach
- ORCID : 0000-0002-7802-944X
Jacques Cadranel
- Function : Author
Audrey Milon
- Function : Author
Stéphane Ederhy
- Function : Author
Thomas Similowski
- Function : Author
- PersonId : 952396
- IdHAL : thomassimilowski
- ORCID : 0000-0003-2868-9279
- IdRef : 034896775
Douglas Johnson
- Function : Author
- PersonId : 1230737
- ORCID : 0000-0002-6390-773X
Ian Pizzo
- Function : Author
Toniemarie Catalan
- Function : Author
Olivier Benveniste
- Function : Author
- PersonId : 1007551
- IdHAL : olivier-benveniste
- ORCID : 0000-0002-1167-5797
Salim Hayek
- Function : Author
- PersonId : 1341005
- ORCID : 0000-0003-0180-349X
Yves Allenbach
- Function : Author
Michelle Rosenzwajg
- Function : Author
Charles Dolladille
- Function : Author
Joe-Elie Salem
- Function : Author
- PersonId : 777251
- IdHAL : joe-elie-salem
- ORCID : 0000-0002-0331-3307
- IdRef : 160947227
Abstract
Immune checkpoint inhibitors (ICI) have transformed the therapeutic landscape in oncology. However, ICI can induce uncommon life-threatening autoimmune T-cell-mediated myotoxicities, including myocarditis and myositis. The thymus plays a critical role in T cell maturation. Here we demonstrate that thymic alterations are associated with increased incidence and severity of ICI myotoxicities. First, using the international pharmacovigilance database VigiBase, the Assistance Publique Hôpitaux de Paris–Sorbonne University data warehouse (Paris, France) and a meta-analysis of clinical trials, we show that ICI treatment of thymic epithelial tumors (TET, and particularly thymoma) was more frequently associated with ICI myotoxicities than other ICI-treated cancers. Second, in an international ICI myocarditis registry, we established that myocarditis occurred earlier after ICI initiation in patients with TET (including active or prior history of TET) compared to other cancers and was more severe in terms of life-threatening arrythmias and concurrent myositis, leading to respiratory muscle failure and death. Lastly, we show that presence of anti-acetylcholine-receptor antibodies (a biological proxy of thymic-associated autoimmunity) was more prevalent in patients with ICI myocarditis than in ICI-treated control patients. Altogether, our results highlight that thymic alterations are associated with incidence and seriousness of ICI myotoxicities. Clinico-radio-biological workup evaluating the thymus may help in predicting ICI myotoxicities.