Abstract 687: Targeting tumor-promoting neuroblastoma microenvironment: inhibiton of tumor development and progression by targeting mPGES-1 expressed by cancer associated fibroblasts

Abstract

Abstract Background: High-risk neuroblastomas present a tumor promoting microenvironment with infiltrating cancer associated fibroblasts (CAFs) expressing the mPGES-1 enzyme, essential for prostaglandin E2 (PGE2) synthesis regulating tumor inflammation and immune suppression, angiogenesis, genetic instability, tumor progression and therapy resistance. We investigated the impact of novel therapy targeting the COX/mPGES-1/PGE2 pathway. Methods: Human neuroblastomas were investigated for immunosuppressive microenvironment and expression of the COX/mPGES-1/PGE2/EP-receptor pathway. High-risk in vivo models, human 11q-deleted xenografts and transgenic MYCN-driven tumors, were treated with a novel specific mPGES-1 inhibitor. Tumor-fibroblast co-cultures examined cell migration. Inflammatory lipid mediators were analyzed by LC-MS/MS. Tumor tissues were analyzed by immunohistochemistry, immunofluorescence and FACS. Results: Tumor microenvironment in human high-risk neuroblastomas and both 11q-deleted xenografts and MYCN-driven transgenic mice displayed mPGES-1 expression in PDGFRb+ cancer associated fibroblasts. MPGES-1 expression correlated with high-risk neuroblastoma prognosis and infiltration of tumor-promoting macrophages with M2-polarization markers CD163 and CD206. The inflammatory regulator STAT3 was active in mPGES-1 expressing CAFs. Expression of the inflammatory COX/mPGES-1/PGE2/EP-receptor pathway in experimental tumors resembled high-risk primary human neuroblastomas. Targeting mPGES-1 with a novel compound decreased PGE2, induced M1 polarization of macrophages, decreased cancer associated fibroblasts and reduced angiogenesis significantly in treated tumors. Tumor development in the xenograft model was delayed and growth of established xenografts and transgenic tumors was significantly decreased by non-toxic treatment in vivo when compared to neuroblastoma tumors in untreated animals. Tumor cell stimulated CAF migration and infiltration was inhibited by targeting mPGES-1. Conclusions: Tumor-promoting inflammation and suppression of anti-tumor immunity in neuroblastoma is mediated through prostaglandin E2 and STAT3 expression in cancer associated fibroblasts in the tumor microenvironment. Early targeting of mPGES-1 may inhibit CAF infiltration and tumor development. This novel tumor treatment targeting mPGES-1 decreases inflammatory mediators, modulates tumor-promoting microenvironment and inhibits significantly aggressive tumor growth and progression. We conclude that treatment targeting non-malignant cells in the neuroblastoma microenvironment may constitute a novel clinical therapeutic approach. Citation Format: Anna Kock, Karin Larsson, Nina Eissler, Filip Bergqvist, Joan Rauf, Marina Korotkova, John-Inge Johnsen, Per-Johan Jakobsson, Per Kogner. Targeting tumor-promoting neuroblastoma microenvironment: inhibiton of tumor development and progression by targeting mPGES-1 expressed by cancer associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 687. doi:10.1158/1538-7445.AM2017-687