Abstract 1233: Myeloperoxidase (MPO) activity in myeloid-derived suppressor cells (MDSCs): effects on anticancer drug activity

Abstract

Abstract In cancer, suppression of host immunity is related, in part, to immature myeloid-derived suppressor cells (MDSCs) expanded in response to various tumor- or stroma-derived factors. Here, the expression and activity of myeloperoxidase (MPO) was examined in both granulocytic (PMN) and monocytic (M) MDSC subsets recovered from the spleens of 4T1 tumor-bearing mice, as well as interferon regulatory factor-8 (IRF8) knockout mice (IRF8-/-) which develop high levels of MDSCs due to IRF8-deficiency. Phenotypically identical cells from non-tumor-bearing mice served as controls. In addition, the role of MPO in PMN-MDSCs as a determinant of DNA damage induced by the anticancer agents etoposide (VP-16), camptothecin (CPT) and parthenolide (PTL), was evaluated for potential immunomodulatory effects. MPO protein content was ~4-fold greater in PMN-MDSCs from tumor-bearing compared to non-tumor-bearing mice, while MPO specific activity was equivalent in these two populations. MPO protein content in PMN-MDSCs from IRF8-/- mice was at least comparable to levels found in tumor-bearing hosts. In both IRF8-/- and tumor-bearing mice, PMN-MDSCs contained 5-10-fold greater MPO protein and overall enzyme activity compared to isolated M-MDSCs. VP-16 (5 µM)- and PTL (100 µM)-induced DNA strand breaks were 4-fold greater in PMN- compared to M-MDSCs from tumor-bearing mice. In addition, the heme-synthesis inhibitor, succinylacetone (SA) reduced MPO activity 2-3-fold in PMN-MDSCs from tumor-bearing mice with a corresponding decrease in drug-induced DNA damage for both VP-16 and PTL with no effect on CPT-induced DNA damage. The antioxidant dehydroascorbate decreased VP-16-induced DNA damage in PMN-MDSCs containing MPO activity, but not in those cells pre-incubated with SA to deplete MPO. These results indicate that MPO-dependent activation of VP-16 and PTL enhance DNA damage. Antioxidant protection against VP-16-induced DNA damage is consistent with MPO-mediated oxidative activation of VP-16 to a redox-cycling phenoxyl radical (Mol. Pharmacol. 79: 479-487, 2011). Overall, these results suggest that: 1) PTL may be useful to eliminate PMN-MDSCs; 2) MPO activation of VP-16 in PMN-MDSCs may be deleterious via oxidative DNA damage resulting in mixed-lineage leukemia (MLL) gene rearrangements known to be causal for therapy-related myeloid leukemias. Support: CA172105; CA090787; CA140622 Citation Format: Jack C. Yalowich, Ragu Kanagasabai, Colleen S. Netherby, Michelle N. Messmer, Scott I. Abrams. Myeloperoxidase (MPO) activity in myeloid-derived suppressor cells (MDSCs): effects on anticancer drug activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1233.