Abstract
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-1β 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 NLRP3high 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-nitroquinoline-1-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-1β, 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.
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Abbreviations
- 4NQO:
-
4-Nitroquinoline-1-oxide
- CM:
-
Cultured medium
- HNSCC:
-
Head and neck squamous cell carcinoma
- MDSCs:
-
Myeloid-derived suppressor cells
- NLRP3:
-
NOD-like receptor family pyrin domain-containing 3
- OS:
-
Overall survival
- PBMCs:
-
Peripheral blood mononuclear cells
- PDA:
-
Pancreatic ductal adenocarcinoma
- TAMs:
-
Tumor-associated macrophages
- TCGA:
-
The cancer genome atlas
- TME:
-
Tumor microenvironment
- TILs:
-
Tumor-infiltrating lymphocytes
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Acknowledgements
Thanks to Shuyan Liang and Juan Zhang from Wuhan Biobank Co.,Ltd for their excellent technical assistance on flow cytometry.
Funding
This work was supported by National Natural Science Foundation of China (82103670, 81972548, 82072996, 81874131), Fundamental Research Funds for the Central Universities (2042021kf0173).
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CL, SZJ and BLL conceptualized the study. CL, WSC and ML developed methodology. CL, WSC and ML performed the experiments. CL and HCF analyzed data. CL, SZJ and BLL wrote the manuscript. All authors contributed to the article and approved the submitted version.
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All animal studies were approved by the Institutional Animal Care and Use Committees at the School and Hospital of Stomatology of Wuhan University (S07918040F and S07922050F). All the human samples were collected from the School and Hospital of Stomatology, Wuhan University, and all experiments were approved by the Medical Ethics Committee (2014LUNSHENZI06, 2016LUNSHENZI62 and 2019LUNSHENZIA24).
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Chen, L., Wan, SC., Mao, L. et al. NLRP3 in tumor-associated macrophages predicts a poor prognosis and promotes tumor growth in head and neck squamous cell carcinoma. Cancer Immunol Immunother 72, 1647–1660 (2023). https://doi.org/10.1007/s00262-022-03357-4
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DOI: https://doi.org/10.1007/s00262-022-03357-4