Cardioprotective Paraoxonase 2 Enhances The Tumoricidal Activity Of Natural Killer Cells In A Paracrine Manner

Background: Immune system can recognize the neoplastic cells and target them for destruction through tumoricidal process. Further, immune cell dysfunction leads to escape of cancer cells from immune recognition, lead to the initiation and progression of tumor formation. Clinical shreds of evidence suggest that the presence of intratumoral immune cells correlates with improved progression free and overall survival among patients with ovarian carcinoma and provide evidence of activation of antitumor mechanisms. Hence identification of drugs that target the cancer cells as well as activate the immune cells is a sound strategy for cancer therapy. Paraoxonase 2 (PON2) is a membrane-associated lactonase with lipid transport, anti-oxidant and phagocytosis/efferocytosis properties. PON2 deficiency aggravates systemic inflammation, and causes the metabolic associated diseases. Recently we have reported that overexpression of PON2 reduces the ovarian cells proliferation and tumor formation by reducing IGF-1 production and its signaling pathway. Further, using microarray based experiment, we have identified several pathways that modulate the immune cells function such as activation of Natural Killer (NK) cells, dendritic cell maturation, B cells activation, and communication between innate and an adaptive cells signaling pathway were regulated by PON2. Hypothesis: PON2 enhances tumoricidal activity in a paracrine fashion. Methods and Results:NK cells were isolated from control C57BL/6 and purity was assessed with flow cytometry using FITC anti mouse CD49B and results revealed that 95 % of NK cells population. NK cells treated with condition medium from ID8hPON2 (human PON2 overexpressed in mouse ovarian cancer cell line) show an increase in tumoricidal activity compared to condition medium from ID8EV. Neither ID8hPON2 nor ID8EV condition medium affects the viability of NK cells. Moreover, there is no difference in CD49B positive staining in the tumor microenvironment between ID8EV and ID8hPON2 cells receiving mice. Condition medium obtained from ID8hPON2 ID8EV group shows increases the interleukin 18 level and neutralizing antibody against IL18 fail to induce the tumoricidal activity indicating mechanistically PON2 enhances the tumoricidal activity via IL18 dependent manner. Furthermore, IL18 levels are increased in tumor micro environment. PON2 increase the IL18 through transactivation of c-Myc gene that are independent of mitochondrial function. Conclusion: Taken together, our study for the first time showed that PON2 enhances the tumerocidal activity via paracrine manner by upregulating IL18 and PON2 could be used as conventional as well as immunotherapy for ovarian cancer. Citation Format: Asokan Devarajan, Dawoud Sulaiman, Feng Su, Ekambaram Ganapathy, Robin Farias-Eisner, Srinivasa Reddy. Cardioprotective paraoxonase 2 enhances the tumoricidal activity of natural killer cells in a paracrine manner [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3309.