학술논문
Systemic Nos2 Depletion and Cox inhibition limits TNBC disease progression and alters lymphoid cell spatial orientation and density
Document Type
article
Author
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. McVicar; Stephen K. Anderson; Jenny Chang; Sharon A. Glynn; Stefan Ambs; Stephen J. Lockett; David A. Wink
Source
Redox Biology, Vol 58, Iss , Pp 102529- (2022)
Subject
Language
English
ISSN
2213-2317
Abstract
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.