Titre
CD40 Agonist Restores the Antitumor Efficacy of Anti-PD1 Therapy in Muscle-Invasive Bladder Cancer in an IFN I/II-Mediated Manner.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Leblond, M.M.
Auteure/Auteur
Tillé, L.
Auteure/Auteur
Nassiri, S.
Auteure/Auteur
Gilfillan, C.B.
Auteure/Auteur
Imbratta, C.
Auteure/Auteur
Schmittnaegel, M.
Auteure/Auteur
Ries, C.H.
Auteure/Auteur
Speiser, D.E.
Auteure/Auteur
Verdeil, G.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
2326-6074
Statut éditorial
Publié
Date de publication
2020-09
Volume
8
Numéro
9
Première page
1180
Dernière page/numéro d’article
1192
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Bladder cancer is one of the most common malignancies and has poor prognosis for patients with locally advanced, muscle-invasive, disease despite the efficacy of immune checkpoint blockade. To develop more effective immunotherapy strategies, we studied a genetic mouse model carrying deletion of Tp53 and Pten in the bladder, which recapitulates bladder cancer tumorigenesis and gene expression patterns found in patients. We discovered that tumor cells became more malignant and the tumor immune microenvironment evolved from an inflammatory to an immunosuppressive state. Accordingly, treatment with anti-PD1 was ineffective, but resistance to anti-PD1 therapy was overcome by combination with a CD40 agonist (anti-CD40), leading to strong antitumor immune responses. Mechanistically, this combination led to CD8 <sup>+</sup> T-cell recruitment from draining lymph nodes. CD8 <sup>+</sup> T cells induced an IFNγ-dependent repolarization toward M1-like/IFNβ-producing macrophages. CD8 <sup>+</sup> T cells, macrophages, IFN I, and IFN II were all necessary for tumor control, as demonstrated in vivo by the administration of blocking antibodies. Our results identify essential cross-talk between innate and adaptive immunity to control tumor development in a model representative of anti-PD1-resistant human bladder cancer and provide scientific rationale to target CD40 in combination with blocking antibodies, such as anti-PD1/PD-L1, for muscle-invasive bladder cancer.
PID Serval
serval:BIB_03172EE2E8EA
PMID
Date de création
2020-07-14T07:52:29.504Z
Date de création dans IRIS
2025-05-20T17:59:35Z
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Nom
Leblond et al 2020.pdf
Version du manuscrit
preprint
Taille
1.43 MB
Format
Adobe PDF
PID Serval
serval:BIB_03172EE2E8EA.P001
Somme de contrôle
(MD5):7040f61119726775757b3bab99a16a16
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Nom
Leblond et al 2020 suppl figures.pdf
Version du manuscrit
preprint
Taille
7.19 MB
Format
Adobe PDF
PID Serval
serval:BIB_03172EE2E8EA.S001
Somme de contrôle
(MD5):94ad42833ca8c63cd5d33b9780f2381b