Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER - Breast Tumors that Lead to Poor Outcome.
Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER - Breast Tumors that Lead to Poor Outcome.
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干扰素-γ 是 ER（导致不良结果的乳腺肿瘤）中 NOS2 和 COX2 表达的典型要素。
DOI：
10.1101/2023.04.06.535916
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
W
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作者：
Cheng,RobertYs;Ridnour,LisaA;Wink,AdelaideL;Gonzalez,AnaL;Femino,EliseL;Rittscher,Helene;Somasundarum,Veena;Heinz,WilliamF;Coutinho,Leandro;CristinaRangel,M;Edmondson,ElijahF;Butcher,Donna;Kinders,RobertJ;Li,Xiaoxian;W
NOS2 和 COX2 肿瘤表达与 ER 乳腺癌不良临床结果之间存在很强的相关性。然而，这些酶诱导肿瘤的机制尚不清楚。癌症基因组图谱 (TCGA) 分析揭示了 NOS2 和 COX2 表达与 Th1 细胞因子之间的相关性。在此，TNBC 细胞的单细胞 RNAseq 分析显示 IFNγ 与 IL1β 或 TNFα 组合可有效诱导 NOS2 和 COX2。鉴于 IFNγ 由溶细胞淋巴细胞分泌，可改善临床结果，因此 IFNγ 的作用呈现出二分性。为了探索这个难题，我们对侵袭性 ER-、TNBC 和 HER2++ 乳腺肿瘤中的肿瘤 NOS2、COX2 和 CD8+T 细胞进行了空间分析。在存在基质限制性 CD8+T 细胞的情况下，表达 NOS2 的肿瘤细胞在肿瘤/基质界面处发生高表达和聚集。表达 COX2 的肿瘤细胞的高表达和聚集延伸到肿瘤核心的免疫沙漠区域，其中 CD8+T 细胞渗透有限或不存在。此外，高NOS2表达的肿瘤细胞靠近卫星增多的区域，表明细胞簇具有更高的转移潜力。进一步的体外实验表明，IFNγ +IL1β/TNFα 增加了治疗肿瘤细胞的伸长和迁移。这种肿瘤微环境的空间分析为了解基质限制性 CD8+T 细胞存在于表达 NOS2 的肿瘤微环境附近的不同区域提供了重要的见解，这些微环境可能会增加转移潜力。
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.