Abstract
Abstract Bexarotene is an oral rexinoic receptor (RXR) agonist that has anti-proliferative activity in breast cancer. RXRs are nuclear receptors that heterodimerize, including with the retinoic acid receptor (RAR), to activate transcription for processes including cellular differentiation, embryonic development, proliferation, and metabolism. We have demonstrated that bexarotene can enhance cancer vaccine efficacy by synergizing with a multi-antigen vaccine to prevent breast cancer in the TgMMTV-neu model. Bexarotene as a single agent increased CD8 T-cell tumor infiltration. We therefore questioned the mechanism by which bexarotene acted as an immunomodulatory drug. Evaluating RXR expression in human peripheral blood monocytes (PBMC) (n=10), we found that RXR is not expressed in NK T-cells or B-cells and in only a minority of CD4+ (5.1 ± 4%) and CD8+ T-cells (3.6 ± 3%). RXR, however, is expressed in 24.9±13% of macrophages, 38.6 ± 14% of plasmacytic dendritic cells (pDC), and 33.1 ± 16% of monocytic dendritic cells (mDC). PMBC treated with increasing doses of bexarotene for 48 hours had increased co-stimulatory CD40 expression on mDC (p=0.0011 between 0 and 20 uM bexarotene) and increased type 1 cytokine release including IL-1β (p=0.03 between 0 and 20 uM bexarotene) and TNFα (p=0.02 between 0 and 20 uM bexarotene) but not type 2 cytokine release of IL-10 (p=0.21) and IL-4 (p=0.5). These data demonstrate that bexarotene can activate type 1 dendritic cells Since activated type 1 dendritic cells are effective at presenting tumor antigens from dying tumor cells, we wanted to determine if bexarotene could increase type 1 immunity in the tumor and thereby enhance the efficacy of paclitaxel chemotherapy. In TgMMTV-neu mice with 100 mm3 established spontaneous tumors (n=5), 50 mg/kg bexarotene inhibited tumor growth by 49% and increased the influx of intratumoral CD8+ T-cells by 61% as compared to PBS treated mice (p=0.01). 10 mg/kg paclitaxel inhibited tumor growth by 57% and increased intratumoral CD8+ T-cells by 45% as compared to PBS treated mice (p=0.003). Paclitaxel and bexarotene together inhibited tumor growth by 83% (p=0.02 compared to bexarotene or paclitaxel alone) and increased intratumoral CD8+ T-cell infiltrate by 58% as compared to PBS treated mice (p=0.01). Bexarotene could both activate type 1 APC and increase the CD8 T-cell infiltrate in the tumor and enhance the efficacy of paclitaxel. These data suggest concurrent adminstration of immunomodulatory bexarotene with paclitaxel may result in augmentation of the anti-tumor activity of chemotherapy in breast cancer. Citation Format: Sasha Elizabeth Stanton, Ekram Gad, Lauren R. Corulli-Rastetter, Mary L. Disis. Bexarotene activates type 1 antigen presenting cells, increases tumor infiltrating CD8 T-cells, and augments the anti-tumor activity of chemotherapy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3687. doi:10.1158/1538-7445.AM2017-3687
Published Version
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