NLRP3 in tumor-associated macrophages predicts a poor prognosis and promotes tumor growth in head and neck squamous cell carcinoma
NLRP3 in tumor-associated macrophages predicts a poor prognosis and promotes tumor growth in head and neck squamous cell carcinoma
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肿瘤相关巨噬细胞中的NLRP3预示头颈部鳞状细胞癌预后不良并促进肿瘤生长
DOI：
10.1007/s00262-022-03357-4
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发表时间：
2022-12-31
影响因子：
5.8
通讯作者：
Sun, Zhi-Jun
中科院分区：
文献类型：
--
作者：
Chen, Lei;Wan, Shu-Cheng;Sun, Zhi-Jun
nod样受体家族pyrin domain-containing 3 （NLRP3）炎性小体在癌症中发挥细胞和组织特异性作用，这意味着它在不同肿瘤或细胞中的激活可能在肿瘤进展中发挥不同的作用。我们之前已经描述了肿瘤固有的NLRP3/IL-1(3)信号在头颈部鳞状细胞癌（HNSCC）中的促肿瘤功能，但其在免疫细胞中的作用尚不清楚。在本研究中，我们发现NLRP3在小鼠和人HNSCC的肿瘤相关巨噬细胞（tumor-associated macrophages, tam）中均有高表达，并且通过免疫组化、免疫荧光和流式细胞术分析发现NLRP3的表达与tam的密度呈正相关。重要的是，NLRP3（高）tam的数量与HNSCC患者较差的总生存有关。敲除NLRP3抑制体外m2样巨噬细胞分化。此外，4-硝基喹啉1-氧化物在nlrp3缺失小鼠中引起的致癌作用降低，肿瘤大小较小。NLRP3基因缺失降低了原肿瘤细胞因子如IL-1(3)、IL-6、IL-10和CCL2的表达，抑制了小鼠HNSCC中tam和髓源性抑制细胞（MDSCs）的积累。因此，tam中NLRP3的激活可能有助于肿瘤进展，并在HNSCC中具有预后意义。
The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome plays cell-and tissue-specific roles in cancer, meaning that its activation in different tumors or cells may play different roles in tumor progression. We have previously described the tumor-promoting function of tumor-intrinsic NLRP3/IL-1(3 signaling in head and neck squamous cell carcinoma (HNSCC), but its role in immune cells remains unclear. In this study, we found that NLRP3 was highly expressed in tumor-associated macrophages (TAMs) in both mouse and human HNSCC, and the expression of NLRP3 was positively correlated with the density of TAMs according to immunohistochemistry, immunofluorescence, and flow cytometry analyses. Importantly, the number of NLRP3(high) TAMs was related to worse overall survival in HNSCC patients. Knocking out NLRP3 inhibited M2-like macrophage differentiation in vitro. Moreover, the carcinogenic effect induced by 4-nitroquinoline1-oxide was decreased in Nlrp3-deficient mice, which had smaller tumor sizes. Genetic depletion of NLRP3 reduced the expression of protumoral cytokines, such as IL-1(3, IL-6, IL-10, and CCL2, and suppressed the accumulation of TAMs and myeloid-derived suppressor cells (MDSCs) in mouse HNSCC. Thus, activation of NLRP3 in TAMs may contribute to tumor progression and have prognostic significance in HNSCC.