Pge2-Ep2/Ep4 Signaling Elicits Mesocar T Cell Immunosuppression in Pancreatic Cancer Publisher Pubmed



Akbari B¹ ; Soltantoyeh T¹ ; Shahosseini Z^{2, 3} ; Jadidiniaragh F⁴ ; Hadjati J¹ ; Brown CE^{5, 6} ; Mirzaei HR^{1, 7, 8} Show Affiliations
Source: Frontiers in Immunology Published:2023

Abstract

Introduction: For many years, surgery, adjuvant and combination chemotherapy have been the cornerstone of pancreatic cancer treatment. Although these approaches have improved patient survival, relapse remains a common occurrence, necessitating the exploration of novel therapeutic strategies. CAR T cell therapies are now showing tremendous success in hematological cancers. However, the clinical efficacy of CAR T cells in solid tumors remained low, notably due to presence of an immunosuppressive tumor microenvironment (TME). Prostaglandin E2, a bioactive lipid metabolite found within the TME, plays a significant role in promoting cancer progression by increasing tumor proliferation, improving angiogenesis, and impairing immune cell’s function. Despite the well-established impact of PGE2 signaling on cancer, its specific effects on CAR T cell therapy remain under investigation. Methods: To address this gap in knowledge the role of PGE2-related genes in cancer tissue and T cells of pancreatic cancer patients were evaluated in-silico. Through our in vitro study, we manufactured fully human functional mesoCAR T cells specific for pancreatic cancer and investigated the influence of PGE2-EP2/EP4 signaling on proliferation, cytotoxicity, and cytokine production of mesoCAR T cells against pancreatic cancer cells. Results: In-silico investigations uncovered a significant negative correlation between PGE2 expression and gene signature of memory T cells. Furthermore, in vitro experiments demonstrated that the activation of PGE2 signaling through EP2 and EP4 receptors suppressed the proliferation and major antitumor functions of mesoCAR T cells. Interestingly, the dual blockade of EP2 and EP4 receptors effectively reversed PGE2-mediated suppression of mesoCAR T cells, while individual receptor antagonists failed to mitigate the PGE2-induced suppression. Discussion: In summary, our findings suggest that mitigating PGE2-EP2/EP4 signaling may be a viable strategy for enhancing CAR T cell activity within the challenging TME, thereby improving the efficacy of CAR T cell therapy in clinical settings. Copyright © 2023 Akbari, Soltantoyeh, Shahosseini, Jadidi-Niaragh, Hadjati, Brown and Mirzaei.