EP2/EP4 targeting prevents tumor-derived PGE2-mediated immunosuppression in cDC2s

• DOI: 10.1093/jleuko/qiae164
• Publication Date: 2024-07-23T12:19:55Z
• Authors: Jorge Cuenca-Esca...; Johanna Bödder; Beatriz Subtil; Marta Sánchez-Sán...; Marcos Vidal-Manr...; Mark W D Sweep; Jonathan A Fauerbach; Alessandra Cambi; Georgina Flórez-Grau; Jolanda M de Vries
• Keywords: Immunosuppression; Prostaglandin E2 receptor

Tumor-derived prostaglandin E2 (PGE2) impairs antitumor immunity by priming suppressive functions on various immune cell types, including dendritic cells (DCs). In this way, tumors mediate DC dysfunction and hamper their antitumoral activity. PGE2 is known to modulate function via signaling through the E-type prostanoid receptor 2 (EP2) EP4. Preclinical studies have demonstrated therapeutic value of targeting EP2/4 in DCs. Ongoing phase 1 clinical trials with EP antagonists shown immunomodulation cancer patients. However, systemic drug administration leads off-target events subsequent side effects. To limit effects targeting, EP2 EP4 were encapsulated polymeric nanoparticles (NPs). study, we evaluated efficacy EP2/4-specific NPs protect conventional type DCs (cDC2s) from tumor-derived different tumor models. We show that signals acquisition a phenotype cDC2s. impaired conversion cDC2s toward state inhibited occurrence features such as interleukin-10 production or ability expand regulatory T cells. Importantly, abolished transition models: melanoma-conditioned media, ascites fluid derived ovarian patients (2-dimensional), upon coculture colorectal patient-derived organoids (3-dimensional). propose PGE2-EP2/4 axis using can achieve system patients, alleviate suppression, thus facilitate development potent