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

Marine M. Leblond, Laure Tillé, Sina Nassiri, Connie B. Gilfillan, Claire Imbratta, Martina Schmittnaegel, Carola H. Ries, Daniel E. Speiser and Grégory Verdeil
Marine M. Leblond
1Department of Oncology, University of Lausanne, Lausanne, Switzerland.
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Laure Tillé
1Department of Oncology, University of Lausanne, Lausanne, Switzerland.
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  • ORCID record for Laure Tillé
Sina Nassiri
1Department of Oncology, University of Lausanne, Lausanne, Switzerland.
2Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland.
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Connie B. Gilfillan
1Department of Oncology, University of Lausanne, Lausanne, Switzerland.
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Claire Imbratta
1Department of Oncology, University of Lausanne, Lausanne, Switzerland.
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Martina Schmittnaegel
3Roche Innovation Center Munich, Pharma Research and Early Development, Penzberg, Germany.
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Carola H. Ries
3Roche Innovation Center Munich, Pharma Research and Early Development, Penzberg, Germany.
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  • ORCID record for Carola H. Ries
Daniel E. Speiser
1Department of Oncology, University of Lausanne, Lausanne, Switzerland.
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Grégory Verdeil
1Department of Oncology, University of Lausanne, Lausanne, Switzerland.
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  • For correspondence: gregory.verdeil@unil.ch
DOI: 10.1158/2326-6066.CIR-19-0826 Published September 2020
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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+ T-cell recruitment from draining lymph nodes. CD8+ T cells induced an IFNγ-dependent repolarization toward M1-like/IFNβ-producing macrophages. CD8+ 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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2020;8:1180–92

  • Received October 22, 2019.
  • Revision received March 24, 2020.
  • Accepted July 1, 2020.
  • Published first July 13, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Immunology Research: 8 (9)
September 2020
Volume 8, Issue 9
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CD40 Agonist Restores the Antitumor Efficacy of Anti-PD1 Therapy in Muscle-Invasive Bladder Cancer in an IFN I/II-Mediated Manner
Marine M. Leblond, Laure Tillé, Sina Nassiri, Connie B. Gilfillan, Claire Imbratta, Martina Schmittnaegel, Carola H. Ries, Daniel E. Speiser and Grégory Verdeil
Cancer Immunol Res September 1 2020 (8) (9) 1180-1192; DOI: 10.1158/2326-6066.CIR-19-0826

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CD40 Agonist Restores the Antitumor Efficacy of Anti-PD1 Therapy in Muscle-Invasive Bladder Cancer in an IFN I/II-Mediated Manner
Marine M. Leblond, Laure Tillé, Sina Nassiri, Connie B. Gilfillan, Claire Imbratta, Martina Schmittnaegel, Carola H. Ries, Daniel E. Speiser and Grégory Verdeil
Cancer Immunol Res September 1 2020 (8) (9) 1180-1192; DOI: 10.1158/2326-6066.CIR-19-0826
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