Abstract
Background: Increased CD8+ T cells in the tumor has shown improved response to therapy and prognosis in breast cancer. Cytotoxic chemotherapies increase immune recognition of the tumor but the effect of chemotherapy on the tumor immune environment is a balance between immune activation and systemic immune suppression. The rexinoic acid receptor agonist bexarotene previously was shown to increase intratumoral CD8+ T cells in TgMMTV-neu transgenic mouse tumors. We therefore determined whether bexarotene could enhance the anti-tumor efficacy of common breast cancer chemotherapies and whether the immune role of bexarotene was contributing to the anti-tumor benefit.
Methods: In two immune competent mouse mammary tumor models, TgMMTV-neu and C3(1)Tag mice, spontaneous tumors were treated with bexarotene and chemotherapy (doxorubicin and paclitaxel in both models, cyclophosphamide in TgMMTV-neu mice, and cisplatin in C3(1)Tag mice) and the tumors were evaluated for CD8 and CD4 T cells. Immune cell populations that express the RXRα receptor were evaluated in human peripheral blood mononuclear cells (PBMC) and the direct role of bexarotene on human dendritic cell populations was evaluated by flow cytometry.
Results: Bexarotene enhanced tumor growth inhibition with all chemotherapies in TgMMTV-neu mice, decreasing growth by 98.1% with doxorubicin, 88% with cyclophosphamide, and 89% with paclitaxel. In C3(1)Tag mice bexarotene and cisplatin decreased tumor growth by 99%. Bexarotene doubled the incidence of CD8+ T cells in the tumors of TgMMTV-neu mice and 5.7 fold increase in C3(1)Tag mice. RXRα receptors were expressed highest in human monocytic (mDC, 33.1±5.7%) and plasmocytic dendritic cells (pDCs 38.6±4.8%), and in 25±4.4% macrophages. Bexarotene activated type I mDCs and pDCs that released IL-1β and TNFα type I cytokines.
Conclusions: Bexarotene enhances the anti-tumor efficacy of cytotoxic chemotherapy in transgenic mouse mammary tumor models and increases intratumoral CD8+ T cells. Bexarotene directly activates type I mDCs and pDCs.
Keywords
Bexarotene, Dendritic cells, Breast cancer, Macrophages