Triple negative breast cancer (TNBC) is associated with lack of expression of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER) and progesterone receptor (PR), and do not respond to hormonal therapy. It is one of the most aggressive breast cancer phenotypes and remains a major health hazard among women with drug resistance being a limiting factor in treatment. Inflammation is a key driver of poor survival among TNBC patients through increase in metastasis and chemo-resistance. We recently demonstrated that co-expression of pro-inflammatory enzymes nitric oxide synthase2 (NOS2) and cycloxygenase2 (COX2) is a powerful prognostic marker of poor outcome (HR=21) among ER(-) patients where we showed that inflammatory loops involving these proteins globally drive major oncogenic pathways [1].

Apart from intramural signaling, the crosstalk of tumor cells with immune cells is a key driver of immuno-suppression. Tumor progression is associated with tumor infiltrating M2 macrophages and Th2 cells leading to immuno-suppression, aberrant activation of cytokines, chemokines and growth factors thus creating a conducive environment for tumor growth and metastasis. Our goal is to modulate the tumor micro-environment (TME) to increase efficacy of current radiation- and immunotherapy.

Radiation therapy is a commonly used treatment option in different types of cancer including breast cancer. Focal radiation limits systemic side effects commonly associated with chemotherapy. It also activates the immune system. A key component of the immune system mediated tumor clearance is cytotoxic CD8 T cells. More recently a study found that increased CD8 cells and Th17 cells are specifically associated with TNBC patients [2]. However, they undergo functional reprogramming in the TME evident from decreased cytotoxic (IFN-γ) and proliferation marker (granzyme B).

We used confocal microscopy and flow-cytometry techniques to investigate the role of NOS2 and COX2 in radiation induced tumor growth delay and metastasis. We also examined the ability of NOS2 and COX2 in regulation of the immune profile of the TME, thus emphasizing their importance in tumor growth and immune-surveillance. Lastly, we evaluated the role of COX2 and NOS2 inhibition using commercially available inhibitors on radiation induced tumor growth delay in murine models of ER- breast cancer.

[1] Basudhar, D. et al, Proceedings of the National Academy of Sciences of the United States of America 2017, 114 (49), 13030-13035.

[2] Gil Del Alcazar, et al., Cancer discovery 2017, 7 (10), 1098-1115.

Note: This abstract was not presented at the meeting.

Citation Format: Debashree Basudhar, Veena Somasundaram, David A. Scheiblin, Robert Y. Cheng, Stephen J. Lockett, David Wink, Lisa A. Ridnour. Role of NOS2-COX2 inhibition in radiation-induced tumor growth delay and immuno-modulation in the tumor micro-environment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1197.