Immunotherapy has now emerged as a promising treatment for metastatic cancer. However, immunotherapy for advanced stage breast carcinoma remains an unmet need. Here we demonstrate that the novel immunomodulator alpha-tocopheryloxyacetic acid (aTEA) synergizes with radiation therapy (RT) in a metastatic murine mammary carcinoma model to improve tumor control more than each individual therapy, and we propose a mechanism based on the stimulation of type I interferons by aTEA.
For in-vivo studies, C57BL/6 mice bearing 4T1 murine mammary carcinoma lesions were treated with dietary aTEA, 20 Gy x 2 fractions ionizing radiotherapy, or the combination of aTEA/RT. Immune activation in animals treated with dietary aTEA was determined by analyzing the percentage of proliferating CD4 and CD8 T cells using a Ki-67 assay. Pulmonary metastatic burden was determined using a clonogenic metastasis assay. For in-vitro studies, murine mammary carcinoma cell lines were treated with aTEA or LPS and whole cell lysates were analyzed by Western blot. Expression of interferon regulation factor 3 (IRF3) pathway proteins, including phospho-TANK binding protein kinase 1 (TBK1) and stimulator of interferon genes (STING) were determined.
Our results indicate that treatment with the combination of aTEA and RT significantly improves tumor control compared to either treatment alone. Combination therapy resulted in complete and durable tumor regression in a subset of animals treated, an effect not observed with aTEA or RT alone. Dietary administration of aTEA stimulates proliferation of both CD4 and CD8 T cells and significantly reduces metastatic burden in 4T1 tumor bearing mice. This immune stimulatory effect of aTEA appears to be mediated by reactive oxygen species (ROS) production and release of type I interferons through a STING mediated pathway.
These preliminary results suggest that the combination of aTEA and ionizing radiation may be a viable therapy for the treatment of metastatic breast carcinoma. This therapeutic combination may provide more durable response to radiotherapy while simultaneously reducing further metastatic spread.
Citation Format: Joshua M. Walker, Diego M. Barragan, Melissa J. Kasiewicz, Charles R. Thomas, William L. Redmond. Alpha-tocopheryloxyacetic acid (aTEA) induced immune activation synergizes with radiation therapy to treat primary and metastatic murine mammary carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1664.