Inflammation-Driven Regulation of PD-L1 and PD-L2, and Their Cross-Interactions with Protective Soluble TNFα Receptors in Human Triple-Negative Breast Cancer

被引:3
|
作者
Baram, Tamir [1 ]
Oren, Nino [1 ]
Erlichman, Nofar [1 ]
Meshel, Tsipi [1 ]
Ben-Baruch, Adit [1 ]
机构
[1] Tel Aviv Univ, Shmunis Sch Biomed & Canc Res, George S Wise Fac Life Sci, IL-6997801 Tel Aviv, Israel
基金
以色列科学基金会;
关键词
breast cancer; interferon gamma; interleukin; 1; beta; PD-L1/PD-L2; pro-inflammatory cytokines; soluble TNFR1/soluble TNFR2; tumor necrosis factor alpha; TUMOR-ASSOCIATED MACROPHAGES; NF-KAPPA-B; MOLECULAR PORTRAITS; INTERFERON-GAMMA; IFN-GAMMA; T-CELLS; INTERLEUKIN-1-BETA; EXPRESSION; NEUTRALIZATION; IDENTIFICATION;
D O I
10.3390/cancers14143513
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Pro-inflammatory cytokines play key roles in elevating cancer progression in triple-negative breast cancer (TNBC). We demonstrate that specific combinations between TNF alpha, IL-1 beta and IFN gamma up-regulated the proportion of human TNBC cells co-expressing the inhibitory immune checkpoints PD-L1 and PD-L2: TNF alpha + IL-1 beta in MDA-MB-231 cells and IFN gamma + IL-1 beta in BT-549 cells; in the latter cells, the process depended entirely on STAT1 activation, with no involvement of p65 (CRISPR-Cas9 experiments). Highly significant associations between the pro-inflammatory cytokines and PD-L1/PD-L2 expression were revealed in the TCGA dataset of basal-like breast cancer patients. In parallel, we found that the pro-inflammatory cytokines regulated the expression of the soluble receptors of tumor necrosis factor alpha (TNF alpha), namely sTNFR1 and sTNFR2; moreover, we revealed that sTNFR1 and sTNFR2 serve as anti-metastatic and protective factors in TNBC, reducing the TNF alpha-induced production of inflammatory pro-metastatic chemokines (CXCL8, CXCL1, CCL5) by TNBC cells. Importantly, we found that in the context of inflammatory stimulation and also without exposure to pro-inflammatory cytokines, elevated levels of PD-L1 have down-regulated the production of anti-tumor sTNFR1 and sTNFR2. These findings suggest that in addition to its immune-suppressive activities, PD-L1 may promote disease course in TNBC by inhibiting the protective effects of sTNFR1 and sTNFR2.
引用
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页数:28
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