Systemic Nos2 Depletion and Cox inhibition limits TNBC disease progression and alters lymphoid cell spatial orientation and density

Veena Somasundaram, Lisa A Ridnour, Robert Ys Cheng, Abigail J Walke, Noemi Kedei, Dibyangana D Bhattacharyya, Adelaide L Wink, Elijah F Edmondson, Donna Butcher, Andrew C Warner, Tiffany H Dorsey, David A Scheiblin, William Heinz, Richard J Bryant, Robert J Kinders, Stanley Lipkowitz, Stephen Tc Wong, Milind Pore, Stephen M Hewitt, Daniel W McVicarStephen K Anderson, Jenny Chang, Sharon A Glynn, Stefan Ambs, Stephen J Lockett, David A Wink

Research output: Contribution to journalArticlepeer-review


Antitumor immune polarization is a key predictor of clinical outcomes to cancer therapy. An emerging concept influencing clinical outcome involves the spatial location of CD8 + T cells, within the tumor. Our earlier work demonstrated immunosuppressive effects of NOS2 and COX2 tumor expression. Here, we show that NOS2/COX2 levels influence both the polarization and spatial location of lymphoid cells including CD8 + T cells. Importantly, elevated tumor NOS2/COX2 correlated with exclusion of CD8 + T cells from the tumor epithelium. In contrast, tumors expressing low NOS2/COX2 had increased CD8 + T cell penetration into the tumor epithelium. Consistent with a causative relationship between these observations, pharmacological inhibition of COX2 with indomethacin dramatically reduced tumor growth of the 4T1 model of TNBC in both WT and Nos2 - mice. This regimen led to complete tumor regression in ∼20-25% of tumor-bearing Nos2 - mice, and these animals were resistant to tumor rechallenge. Th1 cytokines were elevated in the blood of treated mice and intratumoral CD4 + and CD8 + T cells were higher in mice that received indomethacin when compared to control untreated mice. Multiplex immunofluorescence imaging confirmed our phenotyping results and demonstrated that targeted Nos2/Cox2 blockade improved CD8 + T cell penetration into the 4T1 tumor core. These findings are consistent with our observations in low NOS2/COX2 expressing breast tumors proving that COX2 activity is responsible for limiting the spatial distribution of effector T cells in TNBC. Together these results suggest that clinically available NSAID's may provide a cost-effective, novel immunotherapeutic approach for treatment of aggressive tumors including triple negative breast cancer.

Original languageEnglish (US)
Pages (from-to)102529
JournalRedox Biology
StatePublished - Dec 2022


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