Interferon-gamma is quintessential for NOS2 and COX2 expression in ER- breast tumors that lead to poor outcome

• Authors: Robert YS Cheng, National Institutes of Health, Frederick, MD; Lisa A Ridnour, National Institutes of Health, Frederick, MD; Adelaide L Wink, National Cancer Institute, Frederick, MD; Ana L Gonzalez, National Institutes of Health, Frederick, MD; Elise L Femino, National Institutes of Health, Frederick, MD; Helene Rittscher, National Institutes of Health, Frederick, MD; Veena Somasundaram, National Institutes of Health, Frederick, MD; William F Heinz, National Cancer Institute, Frederick, MD; Leandro Coutinho, Universidade de São Paulo; Cristina M Rangel, Universidade de São Paulo; Elijah F Edmondson, National Cancer Institute,Frederick, MD; Donna Butcher, National Cancer Institute,Frederick, MD; Robert J Kinders, National Cancer Institute,Frederick, MD; Xiaoxian Li, Emory University; Stephen TC Wong, Houston Methodist Hospital and Weill Cornell Medicine,; Daniel W McVicar, National Institutes of Health, Frederick, MD; Stephen K Anderson, National Institutes of Health, Frederick, MD; Milind Pore, Frederick National Laboratory for Cancer Research, Frederick, MD; Stephen M Hewitt, National Institutes of Health, Frederick, MD; Timothy R Billiar, University of Pittsburgh; Sharon A Glynn, University of Galway; Jenny C Chang, Houston Methodist Hospital and Weill Cornell Medicine; Stephen J Lockett, National Cancer Institute, Frederick, MD; Stefan Ambs, NIH, Bethesda, MD; David A Wink, National Institutes of Health, Frederick, MD
• Journal Title: CELL DEATH & DISEASE
• Volume: Volume 14, Number 5
• Publisher: SPRINGERNATURE | 2023-05-11, Pages 319-319
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1038/s41419-023-05834-9
• Subjects: Health Sciences, Pathology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Cell Biology; NITRIC-OXIDE SYNTHASE; CANCER; SURVIVAL; PATHWAYS; CELLS

Abstract

A strong correlation between NOS2 and COX2 tumor expression and poor clinical outcomes in ER breast cancer has been established. However, the mechanisms of tumor induction of these enzymes are unclear. Analysis of The Cancer Genome Atlas (TCGA) revealed correlations between NOS2 and COX2 expression and Th1 cytokines. Herein, single-cell RNAseq analysis of TNBC cells shows potent NOS2 and COX2 induction by IFNγ combined with IL1β or TNFα. Given that IFNγ is secreted by cytolytic lymphocytes, which improve clinical outcomes, this role of IFNγ presents a dichotomy. To explore this conundrum, tumor NOS2, COX2, and CD8+ T cells were spatially analyzed in aggressive ER–, TNBC, and HER2 + breast tumors. High expression and clustering of NOS2-expressing tumor cells occurred at the tumor/stroma interface in the presence of stroma-restricted CD8+ T cells. High expression and clustering of COX2-expressing tumor cells extended into immune desert regions in the tumor core where CD8+ T cell penetration was limited or absent. Moreover, high NOS2-expressing tumor cells were proximal to areas with increased satellitosis, suggestive of cell clusters with a higher metastatic potential. Further in vitro experiments revealed that IFNγ + IL1β/TNFα increased the elongation and migration of treated tumor cells. This spatial analysis of the tumor microenvironment provides important insight into distinct neighborhoods where stroma-restricted CD8+ T cells exist proximal to NOS2-expressing tumor niches that could have increased metastatic potential.