| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
|
| Zdroj: |
Redox Biology, Vol 58, Iss , Pp 102529- (2022) |
| Druh dokumentu: |
article |
| ISSN: |
2213-2317 |
| DOI: |
10.1016/j.redox.2022.102529 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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