Abstract 150: Role of reactive oxygen species in doxorubicin-induced apoptosis of myeloid-derived suppressor cells

Abstract

Abstract The expansion of myeloid-derived suppressor cells (MDSC) in the blood, secondary lymphoid organs and tumor beds in animal cancer models and in patients with many types of cancers participates to the immunosuppressive environment associated with the development of tumors. MDSC frequency correlates with the disease stage and prognosis. MDSC can not only impair innate and adaptive antitumor immune responses, but these cell also contribute to enhance tumor angiogenesis and metastatic potential. The therapeutic targeting of MDSC (depletion,functional inactivation or differentiation into pro-inflammatory cells) promotes the efficacy of immunotherapeutic interventions. Conventional anticancer agents such as docetaxel, gemcitabine or sunitinib have been used to eliminate tumor-induced MDSC. We have observed that the anthracycline doxorubicin can deplete MDSC that expanded in the murine mammary tumor models 4T1 and EMT6 and in the EL4 thymoma model. Doxorubicin-mediated elimination of MDSC is associated with increased T and NK cell activity and the combination of this drug with adoptive T lymphocyte transfer impairs tumor development and metastatic spreading. We here present results indicating that doxorubicin-mediated apoptosis of MDSC may depend on an increased production of reactive oxygen species (ROS) by these cells. MDSC from gp91-/- mice (lacking the gp91phox glycosylated subunit of the NADPH oxidase flavocytochrome b558, responsible for the production of superoxide ion O2·-) were less sensitive to doxorubicin-induced cell death than their wild-type counterparts. Consistently, the effects of doxorubicin on MDSC were partially impaired in tumor-bearing gp91-/- animals compared to wild-type mice. Interestingly the level of ROS in CD4+ or CD8+ T and NK cells were low and unchanged by doxorubicin administration. These observations may partly explain the selective effects of this chemotherapeutic agent on immunosuppressive MDSC while effector lymphocytes are spared and the subsequent increased in the effector to suppressor cell ratios, resulting in a mitigated immunosuppressive tumor environment. Citation Format: Darya Alizadeh, Emmanuel Katsanis, Nicolas Larmonier. Role of reactive oxygen species in doxorubicin-induced apoptosis of myeloid-derived suppressor cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 150. doi:10.1158/1538-7445.AM2014-150