Systemic Nos2 Depletion and Cox inhibition limits TNBC disease progression and alters lymphoid cell spatial orientation and density
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
Affiliations
Veena Somasundaram
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
Lisa A. Ridnour
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
Robert YS. Cheng
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
Abigail J. Walke
Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD, USA
Noemi Kedei
Collaborative Protein Technology Resource Nanoscale Protein Analysis, Office of Science Technology Resources, CCR, NCI, NIH, Bethesda, MD, USA
Dibyangana D. Bhattacharyya
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
Adelaide L. Wink
Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD, USA
Elijah F. Edmondson
Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for NCI, Frederick, MD, USA
Donna Butcher
Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for NCI, Frederick, MD, USA
Andrew C. Warner
Molecular Histopathology Laboratories, Leidos Biomedical Research Inc. for NCI, Frederick, MD, USA
Tiffany H. Dorsey
Laboratory of Human Carcinogenesis, CCR, NCI, NIH, Bethesda, MD, USA
David A. Scheiblin
Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD, USA
William Heinz
Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD, USA
Richard J. Bryant
Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK
Robert J. Kinders
Office of the Director, Division of Cancer Treatment and Diagnosis, NCI, Frederick, MD, USA
Stanley Lipkowitz
Women’s Malignancy Branch CCR, NCI, NIH, Bethesda, MD, USA
Stephen TC. Wong
Systems Medicine and Bioengineering, Houston Methodist Neal Cancer Center and Weill Cornell Medical College, Houston, TX, USA
Milind Pore
Imaging Mass Cytometry Frederick National Laboratory for Cancer Research, USA
Stephen M. Hewitt
Laboratory of Pathology CCR, NCI, NIH, USA
Daniel W. McVicar
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA
Stephen K. Anderson
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA; Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
Jenny Chang
Mary and Ron Neal Cancer Center, Houston Methodist Weill Cornell Medical College, Houston, TX, USA
Sharon A. Glynn
Discipline of Pathology, Lambe Institute for Translational Research, School of Medicine, University of Galway, Galway, H91 TK33, Ireland
Stefan Ambs
Laboratory of Human Carcinogenesis, CCR, NCI, NIH, Bethesda, MD, USA
Stephen J. Lockett
Optical Microscopy and Analysis Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. for the National Cancer Institute, Frederick, MD, USA; Corresponding author. 560 Chandler St Frederick, MD, USA.
David A. Wink
Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA; Corresponding author. 567 Palacky St Frederick, MD, USA.
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.
