Systemic Nos2 Depletion and Cox inhibition limits TNBC disease progression and alters lymphoid cell spatial orientation and density

Somasundaram, Veena; Ridnour, Lisa A.; Cheng, Robert; Walke, Abigail; Kedei, Noémi; Bhattacharyya, Dibyangana; Wink, Adelaide L; Edmondson, Elijah F.; Butcher, Donna; Warner, Andrew C.; Dorsey, Tiffany H.; Scheiblin, David A.; Heinz, William F.; Bryant, Richard J.; Kinders, Robert J.; Lipkowitz, Stanley; Wong, Stephen T.C.; Pore, Milind; Hewitt, Stephen M.; McVicar, Daniel W.; Anderson, Stephen; Chang, Jenny C.; Glynn, Sharon A.; Ambs, Stefan; Lockett, Stephen; Wink, David A.

doi:10.1016/j.redox.2022.102529

Cited by 15 publications

(22 citation statements)

References 48 publications

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“…While COX2 is expressed at the edge of immune deserts, its expression is abated deeper at the core of immune deserts. These observations could indicate that COX2/PGE2 may serve as a barrier preventing CD8 + T cell infiltration into the tumor core, thus facilitating the development of an immune desert, which is consistent with increased CD8 + T cell penetration to the core associated with COX inhibition by NSAID treatment (10). These observations further support a role of tumor NOS2/COX2 expression during progression from inflamed foci to immune desert regions.…”

Section: Resultssupporting

confidence: 52%

“…Our earlier findings demonstrated correlations between tumor NOS2/COX2 and the spatial orientation of CD8 + T cell in breast tumors, as well as tumor budding or satellitosis, which is an index of tumor invasiveness. We extended these earlier findings by examining the spatial localization of CD8 + T cells in Deceased vs Alive patient tumors (10, 13). Because NOS2/COX2 products NO/PGE2 have antagonistic effects on T effector cell function, NOS2/CD8 and COX2/CD8 ratios were quantified and found to be significantly elevated in tumors from Deceased patients, for both total and cytolytic (CD8 + PD1 - ) CD8 + T cell populations (Fig.…”

Section: Resultsmentioning

confidence: 71%

“…5B CD44v6 all, EpCAM all). Given that CD44v6 is expressed on lymphocytes and modulates their functional activity (25) and that tumor NOS2/COX2 expression modulates CD8 + T cell penetration into the tumor core (10), potential roles for tumor NOS2/COX2 relative to CD44v6 and EpCAM expression were evaluated by comparing ratios of tumor NOS2/COX2 to CD44v6 and EpCAM. Toward this end, the ratios of NOS2/CD44v6, NOS2/EpCAM, COX2/CD44v6, and COX2/EpCAM were significantly elevated in Deceased patient tumors when compared to Alive patient tumors as shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Many studies have shown that COX2-derived PGE2 and NOS2-derived NO promote immunosuppression in part by limiting activated T effector cells through increased Arg1, IL10, and TGFβ (6–9). In contrast, NOS2/COX2 blockade augmented cytolytic T cells, mature B cells, and neutrophils associated with resistance to 4T1 tumor rechallenge in 4T1 tumor bearing mice (10). Notably, these results are consistent with a recent phase 1/2 clinical trial demonstrating remodeling of the tumor immune microenvironment that involved increased B cells and neutrophils as well as improved overall survival and complete pathological responses in chemoresistant TNBC patients treated with taxol and the NOS inhibitor, L-NMMA (11).…”

Section: Introductionmentioning

confidence: 99%

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NOS2 and COX2 Provide Key Spatial Targets that Determine Outcome in ER-Breast Cancer

Ridnour,

Heinz,

Cheng

et al. 2023

Preprint

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Estrogen receptor-negative (ER-) breast cancer is an aggressive breast cancer subtype with limited therapeutic options. Upregulated expression of both inducible nitric oxide synthase (NOS2) and cyclo-oxygenase (COX2) in breast tumors predicts poor clinical outcomes. Signaling molecules released by these enzymes activate oncogenic pathways, driving cancer stemness, metastasis, and immune suppression. The influence of tumor NOS2/COX2 expression on the landscape of immune markers using multiplex fluorescence imaging of 21 ER-breast tumors were stratified for survival. A powerful relationship between tumor NOS2/COX2 expression and distinct CD8+ T cell phenotypes was observed at 5 years post-diagnosis. These results were confirmed in a validation cohort using gene expression data showing that ratios of NOS2 to CD8 and COX2 to CD8 are strongly associated with poor outcomes in high NOS2/COX2-expressing tumors. Importantly, multiplex imaging identified distinct CD8+ T cell phenotypes relative to tumor NOS2/COX2 expression in Deceased vs Alive patient tumors at 5-year survival. CD8+NOS2-COX2-phenotypes defined fully inflamed tumors with significantly elevated CD8+ T cell infiltration in Alive tumors expressing low NOS2/COX2. In contrast, two distinct phenotypes including inflamed CD8+NOS2+COX2+ regions with stroma-restricted CD8+ T cells and CD8-NOS2-COX2+ immune desert regions with abated CD8+ T cell penetration, were significantly elevated in Deceased tumors with high NOS2/COX2 expression. These results were supported by applying an unsupervised nonlinear dimensionality-reduction technique, UMAP, correlating specific spatial CD8/NOS2/COX2 expression patterns with patient survival. Moreover, spatial analysis of the CD44v6 and EpCAM cancer stem cell (CSC) markers within the CD8/NOS2/COX2 expression landscape revealed positive correlations between EpCAM and inflamed stroma-restricted CD8+NOS2+COX2+ phenotypes at the tumor/stroma interface in deceased patients. Also, positive correlations between CD44v6 and COX2 were identified in immune desert regions in deceased patients. Furthermore, migrating tumor cells were shown to occur only in the CD8-NOS2+COX2+ regions, identifying a metastatic hot spot. Taken together, this study shows the strength of spatial localization analyses of the CD8/NOS2/COX2 landscape, how it shapes the tumor immune microenvironment and the selection of aggressive tumor phenotypes in distinct regions that lead to poor clinical outcomes. This technique could be beneficial for describing tumor niches with increased aggressiveness that may respond to clinically available NOS2/COX2 inhibitors or immune-modulatory agents.

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Section: Resultssupporting

confidence: 52%

Section: Resultsmentioning

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NOS2 and COX2 Provide Key Spatial Targets that Determine Outcome in ER-Breast Cancer

Ridnour,

Heinz,

Cheng

et al. 2023

Preprint

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“…The Siberian Journal of Clinical and Experimental Medicine тальные данные: при перевивном опухолевом росте молочной железы на iNOS-негативных мышах введение ингибитора СОХ-2 приводило не только к регрессии у 20-25% мышей, но и делало их резистентными к повторной перевивке опухолевых клеток, что показывает развитие полноценного противоопухолевого ответа при снятии функций iNOS и СОХ-2 [28].…”

Section: сибирский журнал клинической и экспериментальной медициныunclassified

Inducible NO synthase as a pharmacological target of anti-inflammatory therapy: hope is not lost?

Galagudza

Belsky

Belsky³

2023

SJCEM

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The review is devoted to the current assesment of the role of nitric oxide and inducible NO-synthase in physiological and pathological conditions. The inducible NO-synthase gene expression induction and post-transcriptional regulation of its activity are considered. Data on endogenous inducible NO-synthase inhibitors of are given. An analysis of the clinical trials aimed at studying the clinical efficacy of NO synthase inhibitors was carried out.

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Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity

Purbey,

Seo,

Paul

et al. 2024

Cell Reports

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Systemic Nos2 Depletion and Cox inhibition limits TNBC disease progression and alters lymphoid cell spatial orientation and density

Cited by 15 publications

References 48 publications

NOS2 and COX2 Provide Key Spatial Targets that Determine Outcome in ER-Breast Cancer

NOS2 and COX2 Provide Key Spatial Targets that Determine Outcome in ER-Breast Cancer

Inducible NO synthase as a pharmacological target of anti-inflammatory therapy: hope is not lost?

Opposing tumor-cell-intrinsic and -extrinsic roles of the IRF1 transcription factor in antitumor immunity

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