Abstract P1-03-01: Lipoproteins regulate the effects of macrophages and mesenchymal stem cells on radiation response of inflammatory breast cancer cells

Inflammatory breast cancer (IBC) represents the most aggressive manifestation of breast cancer and results in up to 10% of all breast cancer-related deaths. Lack of IBC-specific targetable drivers suggests involvement of other cell types besides breast tumor epithelial cells. The multidisciplinary treatment of IBC consists of pre-operative neoadjuvant chemotherapy (with targeted agents for Her2- and ER-positive cases), radical mastectomy, followed by radiotherapy. Given that: 1) radiation therapy is a main component in treatment of IBC, 2) we have previously shown that high-density lipoproteins (HDL) mediates outcomes after radiation for IBC, and 3) the possible involvement of tumor micro-environment, it is critically important to understand the role of microenvironment such as tumor-associated macrophages and mesenchymal stem cells (MSC) on radiation response of IBC cells and how this stroma-epithelial crosstalk is regulated by lipoproteins. Here, we used in vitro co-culture system and 2D clonogenic assays of radiation resistance to examine the impact of both polarized human THP1 macrophages and MSCs on radiation response of human IBC cell lines. Further, we determined the effect of MSC-educated THP1 and THP1-educated MSCs, when co-cultured with IBC cells, on radiation response. We also determined the effect of HDL on radiation response of IBC cells co-cultured with M2-polarized (TLR3) MSCs. Our findings demonstrate that while LPS-treated, M1-polarized MSC (TLR4) co-cultured with IBC cell lines SUM149 and IBC3 leads to radio-sensitization, co-culture of IBC cells with Poly (I:C)-treated, M2-polarized MSC (TLR3) leads to radio-resistance of IBC cells. In a similar manner, co-culture of IBC cells with THP1 macrophages polarized to either M1 phenotype (LPS and IFN-γ treated) or M2 phenotype (IL4 and IL13 treated), mediate radio-sensitivity and radio-resistance, respectively, of SUM149 IBC cells. In order to provide a more comprehensive model of macrophage-MSC-IBC crosstalk, we co-cultured IBC cells with THP1 macrophages that have been previously co-cultured (i.e. "educated") with MSC and compared the effect of MSC-educated THP1 versus non-educated on radiation response of IBC cells. Our data show that MSC-education of THP1 enhances radioresistance of IBC SUM149 and KPL4 cells co-cultured with THP1 cells. In a recent publication, we showed that HDL radiosensitize IBC cells and decrease their self-renewal potential. To expand our recently published findings, here we tested whether HDL co-treatment has any effect on MSC-M2 (TLR3)-mediated radioresistance of IBC cells. Our current findings, show that co-treatment of HDL inhibits MSC-M2-mediated radioresistance of SUM149 IBC cells. In sum, these data suggest that cells within tumor micro-environment such as macrophages and MSCs regulate radiation response of IBC cells and this can be altered by lipoproteins. Citation Format: Rahal OM, Wolfe AR, Larson RA, Ueno NT, Reuben JM, Woodward WW. Lipoproteins regulate the effects of macrophages and mesenchymal stem cells on radiation response of inflammatory breast cancer cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-03-01.