Tailored PGE2 Immunomodulation of moDCs by Nano-Encapsulated EP2/EP4 Antagonists

Abstract

Prostaglandin E2 (PGE2) is an important maturation mediator for dendritic cells (DCs). However, increased PGE2 levels in the tumor exert immunosuppressive effects on DCs by signaling through two E-Prostanoid (EP) receptors: EP2 and EP4. Blocking EP-receptor signaling of PGE2 with antagonists is currently being investigated for clinical applications to enhance anti-tumor immunity. In this study, we investigated a new delivery approach by encapsulating EP2/EP4 antagonists in polymeric nanoparticles. The nanoparticles were characterized for size, antagonist loading, and release. The efficacy of the encapsulated antagonists to block PGE2 signaling was analyzed using monocyte-derived DCs (moDCs). The obtained nanoparticles were sized between 210 and 260 nm. The encapsulation efficacy of the EP2/EP4 antagonists was 20% and 17%, respectively, and was further increased with the co-encapsulation of both antagonists. The treatment of moDCs with co-encapsulation EP2/EP4 antagonists prevented PGE2-induced co-stimulatory marker expression. Even though both antagonists showed a burst release within 15 min at 37 °C, the nanoparticles executed the immunomodulatory effects on moDCs. In summary, we demonstrate the functionality of EP2/EP4 antagonist-loaded nanoparticles to overcome PGE2 modulation of moDCs.

PGE2‐EP4 signaling steers cDC2 maturation toward the induction of suppressive T‐cell responses

“…The expression of co-stimulatory molecules is a hallmark of DC maturation. In moDCs, addition of PGE2 during maturation has been demonstrated to upregulate co-stimulatory markers including CD80, CD86, CD83, and HLA-DR [15,20,23,26]. In line with these reports, we observed that MC+PGE2 upregulated these markers also on human cDC2s.…”

“…3A). Specifically, we employed the aEP2 AH6809 and the aEP4 L161-982, which prevent EP specific PGE2 binding and have previously been used on immune cells [10,15,26,35,48]. MC+PGE2 resulted in the upregulation of CD80, CD83, CD86, HLA-DR, and the co-inhibitory molecule PDL-1 on cDC2s (Fig.…”

“…In addition to this modulation toward immune suppression, PGE2 also confers proinflammatory DC characteristics, including the upregulation of co-stimulatory markers (e.g. CD40, CD80, and CD86) and the antigen-presenting molecule MHC class II, leading to a superior capacity to stimulate and expand T cells [15,20,[23][24][25][26]. Furthermore, it is well-known that PGE2 upregulates CCR7 facilitating DC migration toward lymph nodes [27][28][29][30].…”

Modern Methods of Obtaining Immune Dendritic Cells With Anti-Tumor Potential

“…Як було продемонстровано J. Bоdder і співавт. [72], блокування шляхів сигналювання, опосередкованих через рецептори до ПГЕ2 за допомогою антагоністів до цих рецепторів, запобігало виникненню ПГЕ2-індукованої імуносупресорної активності ДК. W. Zhang і співавт.…”