Abstract B104: Immunomodulatory effect of 15-hydroxy prostaglandin dehydrogenase in colon cancer

Abstract

Abstract Cyclooxygenase-2, the key player in the biosynthesis of prostaglandin-E2 (PGE2) is often upregulated in colon cancer. In addition, TNF-α, the prime regulator of COX-2 and mPGES-1, also contributes to increased synthesis of PGE2. However, 15-hydroxy prostaglandin dehydrogenase, a tumor suppressor playing major role in PGE2 catabolism, is often downregulated in colon cancer. Interestingly, colon cancer patients expressing high levels of cysteinyl leukotriene receptor-2 (CysLT2R) show good prognosis and therefore, we investigated a potential link between CysLT2R-signaling and 15-PGDH in metastatic colon cancer. Elevation of 15-PGDH expression by LTC4, a CysLT2R ligand, exhibited antitumor activity in colon cancer cells with significant phosphorylation of β-catenin with concurrent activation of CASPASE-3 and dramatic downregulation of TNF-α as well as NFκβ1 mRNA expression in HT-29 and Caco-2 colon cancer cells. The interaction between programmed death ligand 1 (PD-L1) and programmed death receptor 1 (PD-1) of cancer cells and T cells, respectively, leads to T-cell inactivation and tumor escape. We observed that recombinant TNF-α stimulated colon cancer cells expressed high PD-L1 compared to the unstimulated counterparts, which was downregulated by LTC4 treatment. Protumorigenic role and association of tumor-associated macrophage (TAMs) with PD-L1 was also evident with increase in CD-47 mRNA expression. Human (SW480, SW620) and mouse (MC-38) colon cancer cells exposed to conditioned media of chemically differentiated THP-1 and RAW 264.7 cells, respectively, showed abundant expression of PD-L1 in both mRNA and protein level along with CD-47 in mRNA level, which was inhibited by LTC4 stimulation via activation of CysLT2R in a 15-PGDH dependent manner. Hence restoration of 15-PGDH expression through CysLT2R-signaling promotes immunomodulatory effect, indicating a promising therapeutic alternative for metastatic colon cancer with high TAM infiltration. Citation Format: Shakti R. Satapathy, Anita Sjolander. Immunomodulatory effect of 15-hydroxy prostaglandin dehydrogenase in colon cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B104.