Abstract 6198: Regulation of cycloxygenase-2 in the tumor micro-environment improves radiation and immunotherapy
Authors: Basudhar Debashree , Somasundaram Veena , Scheiblin David A. , Kedei Noemi , Cheng Robert Y. , Ridnour Lisa A. , McVicar Daniel W. , Lockett Stephen , Wink David A. 
Published: September 2020

In breast cancer (BC), the presence of tumor infiltrating lymphocytes is associated with improved survival. A recent study showed that increased CD8 cells and Th17 cells are specifically associated with triple negative breast cancer (TNBC) patients, a highly aggressive subclass of breast cancer. However, they undergo functional reprogramming in the tumor micro-environment(TME) evident from decreased IFN-γ;; and granzyme B. These immune escape mechanisms contribute to inability of the immune system to control tumor progression. Thus modulation of TME is necessary to effectively target the tumor. Radiation therapy (RT) is commonly used in more than 60% of cancer patients including BC. Focal radiation limits systemic side effects commonly associated with chemotherapy and acts as immune modulator. Eventually the tumor comes out of the growth delay and tends to show more aggressive phenotype. We found that RT induced inflammation associated biomarkers nitric oxide synthase2 (NOS2) and cycloxygenase2 (COX2) in the TME, specifically in the tumor cells.We previously showed that co-expression of pro-inflammatory enzymes NOS2 and COX2is a powerful prognostic indicator of poor outcome (HR=21) among ER-patients which in turn drive major oncogenic pathways. Immunotherapy, on the other hand, is being used as a standard of care in lung cancer. However, currently there is no approved immunotherapy available for BC patients, early data from several ongoing clinical trials show activity in various subclasses of BC including TNBC. It is reported that PD-L1 is high in 20% of TNBCs and COX2 may be involved in its regulation in tumor-infiltrating myeloid cells. This led us to hypothesize that modulation of inflammation associated biomarkers in the TME would increase the efficacy of RT and immunotherapy by amplifying anti-tumor immunity. We investigated the effect of NOS2 or COX2 inhibition using commercially available inhibitor on radiation and αPD-L1 induced tumor growth delay and lung metastases in murine model of TNBC using 4T1 cell line implanted in flank of Balbc mice. Change in immune cell populations in the TME was investigated using confocal microscopy, CO-Detection by indEXing (CODEX) technology and flow-cytometry. We also measured the levels of inflammation associated cytokines in serum. We demonstrated that co-treatment with COX2 inhibitor led to tumor growth delay and reduced metastases compared to conventional therapy by changing the TME to support tumor clearance.

Citation Format: Debashree Basudhar, Veena Somasundaram, David A. Scheiblin, Noemi Kedei, Robert Y. Cheng, Lisa A. Ridnour, Daniel W. McVicar, Stephen Lockett, David A. Wink. Regulation of cycloxygenase-2 in the tumor micro-environment improves radiation and immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6198.