Interferon-gamma is quintessential for NOS2 and COX2 expression in ER- breast tumors that lead to poor outcome
Year: 2023
Type: article
Abstract: A strong correlation between NOS2 and COX2 tumor expression and poor clinical outcomes in ER-breast cancer has been established. However, 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 IFNγpresents 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 elongation and migration of treated tumor cells. This spatial analysis of the tumor microenvironment provides important insight of distinct neighborhoods where stroma-restricted CD8 + T cells exist proximal to NOS2-expressing tumor niches that could have increased metastatic potential.
Source: Cell Death and Disease
Authors: Robert Y. S. Cheng, Lisa A. Ridnour, Adelaide L. Wink, Ana L. Gonzalez, Elise L. Femino, Helene Rittscher, Veena Somasundaram, William F. Heinz, Leandro Coutinho, M. Cristina Rangel, Elijah F. Edmondson, Donna Butcher, Robert J. Kinders, Xiaoxian Li, Stephen T. C. Wong, Daniel W. McVicar, Stephen K. Anderson, Milind Pore, Stephen M. Hewitt, Timothy R. Billiar, Sharon A. Glynn, Jenny C. Chang, Stephen J. Lockett, Stefan Ambs, David A. Wink
Institutions: National Institutes of Health, National Cancer Institute, Center for Cancer Research, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc. (United States), Universidade de São Paulo, Instituto do Câncer do Estado de São Paulo, Emory University, Houston Methodist, Weill Cornell Medicine, University of Pittsburgh Medical Center, Ollscoil na Gaillimhe – University of Galway
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,490
Funders: U.S. Department of Health and Human Services, Breast Cancer Research Foundation, Frederick National Laboratory for Cancer Research, Science Foundation Ireland, Fundação de Amparo à Pesquisa do Estado de São Paulo, National Institutes of Health, European Regional Development Fund, National Cancer Institute
Awards: G1014941162, G1234541941, G1282168403, G1856348807, A New Dimension to Ancient Enemies: Targeting Nitrosative Stress and Human Endogenous Retrovirus K Improved Diagnosis, Chemoprevention and Treatment of High Grade Breast and Prostate Cancer, G2132873222, G2910527101, G3503792436, Targenting stemness as a strategy for treating triple-negative breast cancer, G3841754732, G386607036, G4585269469, G4689185066, G4988656331, CÚRAM - Centre for Research in Medical Devices, G5429246515, G5989595523, G6252953675, G6438247056, G9000162200, G9000192686, G9000255858
OpenAlex ID: W4376138573