Tumor NOS2 and COX2 spatial juxtaposition with CD8+ T cells promote metastatic and cancer stem cell niches that lead to poor outcome in ER− breast cancer

Journal article

Estrogen receptor-negative breast cancer is an aggressive subtype with limited therapeutic options. Elevated nitric oxide synthase (NOS2) and cyclo-oxygenase (COX2) mediates immunosuppression and poor survival in these tumors. Therefore, the influence of tumor NOS2/COX2 on immune architecture was examined in 16 African American and 5 Caucasian ER- tumors. Elevated tumor NOS2/COX2 limited CD8+ T cell infiltration at 5-yr survival. Distinct CD8+/-NOS2+/-COX2+/- phenotypes defining metastatic and cancer stem cell niches, and immune desert regions were identified. These results were supported by an unbiased, unsupervised nonlinear dimensionality-reduction UMAP technique incorporating spatial relations between cells and validated in a separate gene expression cohort using NOS2/CD8 and COX2/CD8 ratios. Additionally, elongated tumor cells were specifically in CD8-NOS2+COX2+ regions, suggesting metastatic hot spots. This work demonstrates predictive power of spatial analyses of CD8/NOS2/COX2 architecture and supports the use of clinically available NOS2/COX2 inhibitors for improved survival in patients with these aggressive tumors.

Authors: Ridnour, LA; Heinz, WF; Cheng, RYS; Wink, AL; Kedei, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for Cancer Research
• Journal: Cancer Research Communications
• Volume: 4
• Issue: 10
• Pages: 2766-2782
• Place of publication: United States
• Publication date: 2024-10-23
• Acceptance date: 2024-09-30
• DOI: 10.1158/2767-9764.crc-24-0235
• EISSN: 2767-9764
• Pmid: 39356141
• Language: English