Abstract
Tumor immunosuppression affects survival and treatment efficacy. Tumor NOS2/COX2 coexpression strongly predicts poor outcome in estrogen receptor–negative (ER–) breast cancer by promoting metastasis, drug resistance, cancer stemness, and immune suppression. Herein, a spatially distinct NOS2/COX2 and CD3+CD8+PD1– T effector (TEff) cell landscape correlated with poor survival in ER– tumors. NOS2 was primarily expressed at the tumor margin, whereas COX2 together with B7H4 was associated with immune desert regions lacking TEff cells, where a higher ratio of tumor NOS2 or COX2 to TEff cells predicted poor survival. Also, programmed cell death ligand 1/programmed cell death 1, regulatory T cells (TRegs), and IDO1 were primarily associated with stroma-restricted TEff cells. Regardless of the survival outcome, CD4+ T cells and macrophages were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to increased CD8+ TEff/CD4+ TReg ratio and CD8+ TEff infiltration while Nos2 deficiency had no significant effect, thus reinforcing our observations that COX2 is an essential component of immunosuppression through CD8+ TEff cell exclusion from the tumor. Our study indicates that tumor NOS2/COX2 expression plays a central role in tumor immune evasion, suggesting that strategies combining clinically available NOS2/COX2 inhibitors with immune therapy could provide effective options for the treatment of aggressive and drug-resistant ER– breast tumors.
Authors
Lisa A. Ridnour, Robert Y.S. Cheng, William F. Heinz, Milind Pore, Ana L. Gonzalez, Elise L. Femino, Rebecca L. Moffat, Adelaide L. Wink, Fatima Imtiaz, Leandro L. Coutinho, Donna Butcher, Elijah F. Edmondson, M. Cristina Rangel, Stephen T.C. Wong, Stanley Lipkowitz, Sharon A. Glynn, Michael P. Vitek, Daniel W. McVicar, Xiaoxian Li, Stephen K. Anderson, Nazareno Paolocci, Stephen M. Hewitt, Stefan Ambs, Timothy R. Billiar, Jenny C. Chang, Stephen J. Lockett, David A. Wink
Figure 2
Cytokine-induced NOS2 and COX2 expression.
