LAUSR

Triple negative breast cancer (TNBC) is considered to be the most aggressive and malignant neoplasm and is highly metastatic in nature. Metastatic TNBC is difficult to treat thus leading to extremely poor survival. The major contributing factor in TNBC progression and resistive nature is its ability to evade the immune surveillance. Modulating the immune system in breast tumors could be an important strategy for cancer therapeutics. The present study evaluates the immune response of atovaquone, an antiprotozoal drug in various TNBC cell lines and its efficacy in three independent in vivo models. In the first experiment, HCC1806 human breast cancer cells were orthotopically implanted in mammary fat of female mice. Oral administration of atovaquone reduced HCC1806 breast tumor growth by 45%. On the other hand, oral administration of atovaquone inhibited the growth of highly aggressive CI66 breast tumors by 70%. Paclitaxel is the first line chemotherapeutic agent for metastatic breast cancer. In third in vivo experiment, 4T1 paclitaxel resistant (4T1R) cells were injected in mice and atovaquone suppressed paclitaxel resistant tumor growth by 42%. Myeloid derived suppressor cells (MDSCs) are known to suppress immune function. Our current results demonstrated 70% and 30% suppression of tumor and blood MDSCs respectively, with atovaquone treatment in mouse bearing HCC1806 tumors. We also observed about 25% reduction in MDSCs with atovaquone treatment in mice with CI66 as well as 4T1R tumors. MDSCs induce regulatory T cells (Treg cells) which are immunosuppressive. Our results showed reduction of Treg cells by 12% and 17% with atovaquone treatment in HCC1806 tumors and in 4T1R tumors respectively. In addition, decrease in TGF-beta (13%) and IL-10 (40%) in HCC1806 tumor lysates was observed by atovaquone, an evidence of reduction in immunosuppressive cytokines produced by MDSCs. It appears that the mechanism of immune suppression of atovaquone by MDSCs in our model may be through TGF-β and IL-10, which are potent immunosuppressive cytokines and induce Treg cells that allow cancer cells to escape from immune surveillance. This is the first report demonstrating that immune modulation by atovaquone treatment is associated with breast tumor growth suppression, prompting further investigation to establish atovaquone as a treatment option for TNBC patients. Citation Format: Nehal Gupta, Stephen Wright, Sanjay Srivastava. Atovaquone suppresses triple negative breast tumor growth by inhibiting myeloid derived suppressor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-125.