CD40 Agonist Restores the Antitumor Efficacy of Anti-PD1 Therapy in Muscle-Invasive Bladder Cancer in an IFN I/II-Mediated Manner.

Details

Serval ID
serval:BIB_03172EE2E8EA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
CD40 Agonist Restores the Antitumor Efficacy of Anti-PD1 Therapy in Muscle-Invasive Bladder Cancer in an IFN I/II-Mediated Manner.
Journal
Cancer immunology research
Author(s)
Leblond M.M., Tillé L., Nassiri S., Gilfillan C.B., Imbratta C., Schmittnaegel M., Ries C.H., Speiser D.E., Verdeil G.
ISSN
2326-6074 (Electronic)
ISSN-L
2326-6066
Publication state
Published
Issued date
09/2020
Peer-reviewed
Oui
Volume
8
Number
9
Pages
1180-1192
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
Keywords
Animals, CD40 Antigens/agonists, CD40 Antigens/immunology, CD40 Antigens/metabolism, Disease Models, Animal, Humans, Immune Checkpoint Inhibitors/pharmacology, Immunotherapy/methods, Mice, Urinary Bladder Neoplasms/immunology, Urinary Bladder Neoplasms/therapy
Pubmed
Web of science
Funding(s)
Swiss National Science Foundation / 310030_182680
Create date
14/07/2020 8:52
Last modification date
16/09/2021 5:40
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