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

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.

Tumor-Associated Macrophages in Bladder Cancer: Biological Role, Impact on Therapeutic Response and Perspectives for Immunotherapy

“…The correlation between TAMs, especially M2-like TAMs, and grade and stage of BCa has been confirmed at the largest scale by RNA-seq on the TCGA MIBC cohort [ 38 ]. In support of this, it was observed in a genetically-engineered mouse model of BCa that TAM number, composed of M2-like TAMs, increases with tumor progression [ 39 ]. However, TAM count is not associated with any other clinicopathological feature such as gender, age, tumor volume or multifocality in BCa [ 26 , 32 , 34 ].…”

CXCL9-expressing tumor-associated macrophages: new players in the fight against cancer

“…Viewed through this lens, promising therapeutic approaches to combine with anti-PD1 therapy include agonizing M3-like cells directly to enhance their function, for instance, using CD40 agonists. [53][54][55] Alternatively, exploiting opportunities to increase the stability of the CXCR3-CXCL9/10 axis may prove promising, for instance, enhancing CXCL10 protein stability by DPP4 inhibition, 29 or preventing the downregulation of CD8 T cell CXCR3 expression by tumor-derived TGFβ. 56 Finally, depletion of mature macrophages may allow for enhanced infiltration of inflammatory monocytes with the potential to differentiate into CXCL9-expressing TAMs, such as has recently been shown using Lif, CD163, Trem2 or Tyro-Axl-Mer receptor antagonists.…”

M1-like TAMs are required for the efficacy of PD-L1/PD-1 blockades in gastric cancer

“…Thus, reprogramming or repolarizing TAMs toward an anti-tumor phenotype could therefore prove a more efficacious approach to augmenting the efficacy of PD-L1/PD-1 blockades in GC. For instance, CD40 antibody is one of the most productive approaches to date, and enhance responses to PD-1 and CTLA-4 antagonists have been observed [43][44][45] In conclusion, immune evasion is an obstacle to successful cancer therapy, which is involved in a series of complex and collaborative mechanisms, such as PD-L1/PD-1 axis, CD80, 86/CTLA-4 axis, antigen presentation deletion, metabolism, and so on. 46 Only when one mechanism plays a crucial role in the immune evasion of this tumor, can the related targeted therapy achieve the clinical therapeutic effect in this tumor.…”