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Blockage of the NLRP3 inflammasome by MCC950 improves anti-tumor immune responses in head and neck squamous cell carcinoma

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Abstract

The NLRP3 inflammasome is a critical innate immune pathway responsible for producing active interleukin (IL)-1β, which is associated with tumor development and immunity. However, the mechanisms regulating the inflammatory microenvironment, tumorigenesis and tumor immunity are unclear. Herein, we show that the NLRP3 inflammasome was over-expressed in human HNSCC tissues and that the IL-1β concentration was increased in the peripheral blood of HNSCC patients. Additionally, elevated NLRP3 inflammasome levels were detected in tumor tissues of Tgfbr1/Pten 2cKO HNSCC mice, and elevated IL-1β levels were detected in the peripheral blood serum, spleen, draining lymph nodes and tumor tissues. Blocking NLRP3 inflammasome activation using MCC950 remarkably reduced IL-1β production in an HNSCC mouse model and reduced the numbers of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). Moreover, inhibiting NLRP3 inflammasome activation increased the numbers of CD4+ and CD8+ T cells in HNSCC mice. Notably, the numbers of exhausted PD-1+ and Tim3+ T cells were significantly reduced. A human HNSCC tissue microarray showed that NLRP3 inflammasome expression was correlated with the expression of CD8 and CD4, the Treg marker Foxp3, the MDSC markers CD11b and CD33, and the TAM markers CD68 and CD163, PD-1 and Tim3. Overall, our results demonstrate that the NLRP3 inflammasome/IL-1β pathway promotes tumorigenesis in HNSCC and inactivation of this pathway delays tumor growth, accompanied by decreased immunosuppressive cell accumulation and an increased number of effector T cells. Thus, inhibition of the tumor microenvironment through the NLRP3 inflammasome/IL-1β pathway may provide a novel approach for HNSCC therapy.

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Abbreviations

NLRP3:

Nod-like receptor protein 3

HNSCC:

Head and neck squamous cell carcinoma

Dys:

Dysplasia

IL-1β:

Interleukin (IL)-1β

TILs:

Tumor-infiltrating lymphocytes

Tregs:

Regulatory T cells

TCGA:

The Cancer Genome Atlas

MDSCs:

Myeloid-derived suppressor cells

TAMs:

Tumor-associated macrophages

PD-1:

Programmed death-1

Tim3:

T cell immunoglobulin mucin-3

ELISA:

Enzyme-linked immunosorbent assay

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Acknowledgements

This work was supported by National Natural Science Foundation of China 81402241, 81672667, 81672668, 81472528, 81472529.

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Author notes

  1. Lei Chen and Cong-Fa Huang contributed equally to this study.

Authors and Affiliations

  1. The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China

    Lei Chen, Cong-Fa Huang, Yi-Cun Li, Wei-Wei Deng, Liang Mao, Lei Wu, Wen-Feng Zhang, Lu Zhang & Zhi-Jun Sun

  2. Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan, China

    Wen-Feng Zhang & Zhi-Jun Sun

  3. Department of Endodontics, School and Hospital of Stomatology, Wuhan University, Wuhan, China

    Lu Zhang

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  1. Lei Chen
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Correspondence to Zhi-Jun Sun.

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Ethical standards

Animal studies were approved and supervised by the Animal Care and Use Committee of Wuhan University. All human studies obtained informed consent from patients at the beginning of the trial and were approved by the Medical Ethics Committee of the Hospital of Stomatology, Wuhan University. The ethical approval number is 2014C66.

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18_2017_2720_MOESM1_ESM.tif

Supplementary Fig. 1. a IL-1B mRNA expression levels from several datasets for Head–Neck cancer versus normal mucosa counterpart. b IL-1B mRNA expression was closely related to NLRP3 in TCGA dataset (p < 0.001, r = 0.3558) (TIFF 1065 kb)

18_2017_2720_MOESM2_ESM.tif

Supplementary Fig. 2. The expression of ASC, caspase-1, and IL-18 were correlated with CD8, PD-1, Tim3 and Treg, MDSC, TAM markers in human HNSCC (TIFF 11065 kb)

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Chen, L., Huang, CF., Li, YC. et al. Blockage of the NLRP3 inflammasome by MCC950 improves anti-tumor immune responses in head and neck squamous cell carcinoma. Cell. Mol. Life Sci. 75, 2045–2058 (2018). https://doi.org/10.1007/s00018-017-2720-9

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