CD40 agonist restores the antitumor efficacy of anti-PD1 therapy in muscle-invasive bladder cancer in an IFN I/II-mediated manner

Bladder Cancer

Leblond MM, et al. Cancer Immunol Res 2020.


Bladder cancer (BC) is one of the most common malignancies and has poor prognosis for patients with locally advanced, muscle-invasive, disease, despite of 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 BC 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 -II were all necessary for tumor control as demonstrated in vivo by the administration of blocking antibodies. Our results identify essential crosstalk between innate and adaptive immunity to control tumor development in a model representative of anti-PD1-resistant human BC and provide scientific rationale to target CD40 in combination with blocking antibodies, such as anti-PD1/PD-L1, for muscle-invasive BC.