Enhanced Immunotherapeutic Efficacy of Anti–PD-L1 Antibody in Combination with an EP4 Antagonist

Abstract

Combination treatment approaches are increasingly considered to overcome resistance to immunotherapy targeting immunoinhibitory molecules such as programmed death (PD)-1 and PD-ligand 1 (PD-L1). Previous studies have demonstrated that the therapeutic efficacy of anti-PD-L1 Abs is enhanced by combination treatment with cyclooxygenase-2 inhibitors, through downregulation of the immunosuppressive eicosanoid PGE 2 , although the underlying mechanism remains unclear. In this study, we show that serum PGE 2 levels are upregulated after anti-PD-L1 Ab administration in a bovine model of immunotherapy and that PGE 2 directly inhibits T cell activation via its receptor E prostanoid (EP) 4. Additionally, anti-PD-L1 Ab induces TNF-a production and TNF-a blockade reduces PGE 2 production in the presence of anti-PD-L1 Ab, suggesting that anti-PD-L1 Ab-induced TNF-a impairs T cell activation by PGE 2 upregulation. Our studies examining the therapeutic potential of the dual blockade of PD-L1 and EP4 in bovine and murine immune cells reveal that the dual blockade of PD-L1 and EP4 significantly enhances Th1 cytokine production in vitro. Finally, we show that the dual blockade decreases tumor volume and prolongs survival in mice inoculated with the murine lymphoma cell line EG7. Altogether, these results suggest that TNF-a induced by anti-PD-L1 Ab treatment is associated with T cell dysfunction via PGE 2 /EP4 pathway and that the dual blockade of PD-L1 and EP4 should be considered as a novel immunotherapy for cancer.

Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment

“…Based on our results from mouse breast cancer models, blockade of PGE2 receptors, which remains less explored in clinical settings than inhibition of COX enzymes (Pannunzio and Coluccia, 2018;Reader et al, 2011), could be an effective approach in prevention and treatment of lung metastasis. Emerging data from multiple mouse models of solid cancers have shown promising effects from the combination of EP4 antagonists and PD1/PD-L1 blockade in inhibiting primary tumor growth (Lu et al, 2021;Peng et al, 2022;Sajiki et al, 2020;Tokumasu et al, 2022;Wang et al, 2021). In our work, dual inhibition of EP2 and EP4 was required to suppress lung metastasis, possibly owing to the potent immunosuppressive lung microenvironment.…”

Exploration of serum biomarkers in dogs with malignant melanoma receiving anti-PD-L1 therapy and potential of COX-2 inhibition for combination therapy

“…In mouse tumor models, COX inhibition by aspirin or celecoxib enhanced the efficacy of anti-PD-1 antibody 28 , implying that inhibition of the COX-2/PGE 2 pathway could be a useful adjuvant to ICI treatment. Indeed, we previously reported that dual blockade of these pathways enhanced ICI therapeutic efficacy in cattle with bovine leukemia virus infection and in a mouse lymphoma model 64 , 65 , suggesting that this combination strategy is applicable across animal species and diseases.…”

Oral administration of E-type prostanoid (EP) 1 receptor antagonist suppresses carcinogenesis and development of prostate cancer via upregulation of apoptosis in an animal model

“…Thus, it is possible that EP2–EP4 antagonists may have chemopreventive and anti-cancer effects in in vivo studies. In recent years, a combination therapy of anti-PD-L1 antibody and EP4 antagonist enhanced anti-tumor growth effects and prolonged survival in mice inoculated with murine lymphoma cells 52 . Finally, we suggest further in vivo studies, including animal experiments, to discuss the usefulness, limitations, and safety of novel therapeutic strategies by inhibition of EP receptor pathways and of combined therapies with such treatments and conventional therapies in PC.…”