Elevated tumor NOS2/COX2 promotes immunosuppressive phenotypes associated with poor survival in ER– breast cancer
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
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
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Research Article Inflammation Oncology

Elevated tumor NOS2/COX2 promotes immunosuppressive phenotypes associated with poor survival in ER– breast cancer

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

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Figure 6

Progression of CD8+ T cell exclusion during the formation of tumor immune deserts.

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Progression of CD8+ T cell exclusion during the formation of tumor immun...
Distinct classes of CD8+ T cell exclusion were observed. (A) Type I: inflamed but stroma-restricted CD8+ T cells (orange) with NOS2 (red) expression at the tumor margin and high COX2 (green) expression deeper into tumor core. Type II: abated CD8+ T cells, low NOS2 expression at the tumor margin, and high COX2 expression deeper into tumor core. Type III: absence of CD8+ T cells with abated NOS2 expression at the tumor margin and low, sparse COX2 expression deeper into tumor core. (B) Differential penetration of CD4+ versus CD8+ T cells into high NOS2/COX2-expressing tumors of deceased patients where both CD4+ and CD8+ T cells remain in the tumor stroma, as shown in fluorescence image, spatial animation (middle), and density heatmap (right). (C) In contrast, CD4+ T cells remain in the tumor stroma while CD8+ T cells penetrate deep into low NOS2/COX2-expressing tumor core of alive patients.