| 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 Warner, Tiffany H Dorsey, David A Scheiblin, William Heinz, Richard J. Bryant, Robert 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 |
| Rok vydání: |
2022 |
| DOI: |
10.1101/2022.06.03.494733 |
| Popis: |
Anti-tumor 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/ COX2 tumor expression. Here, we show that NOS2/COX2 levels influence 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 bothWTandNos2-/-mice. This regimen led to complete tumor regression in ∼20% of tumor-bearingNos2-/-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: |
OpenAIRE |
| Externí odkaz: |
|
