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Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity

Nature Cell Biology volume 22, pages 716–727 (2020)Cite this article

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Abstract

PTEN is a dual-specificity phosphatase that is frequently mutated in human cancer, and its deficiency in cancer has been associated with therapy resistance and poor survival. Although the intrinsic tumour-suppressor function of PTEN has been well established, evidence of its role in the tumour immune microenvironment is lacking. Here, we show that chemotherapy-induced antitumour immune responses and tumour suppression rely on myeloid-cell PTEN, which is essential for chemotherapy-induced activation of the NLRP3 inflammasome and antitumour immunity. PTEN directly interacts with and dephosphorylates NLRP3 to enable NLRP3–ASC interaction, inflammasome assembly and activation. Importantly, supplementation of IL-1β restores chemotherapy sensitivity in mouse myeloid cells with a PTEN deficiency. Clinically, chemotherapy-induced IL-1β production and antitumour immunity in patients with cancer is correlated with PTEN expression in myeloid cells, but not tumour cells. Our results demonstrate that myeloid PTEN can determine chemotherapy responsiveness by promoting NLRP3-dependent antitumour immunity and suggest that myeloid PTEN might be a potential biomarker to predict chemotherapy responses.

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Fig. 1: Chemotherapy efficacy relies on myeloid-cell PTEN.
Fig. 2: Myeloid-cell PTEN is essential for chemotherapy-induced inflammasome activation.
Fig. 3: PTEN and its protein-phosphatase activity are required for NLRP3 activation.
Fig. 4: PTEN directly interacts with NLRP3.
Fig. 5: PTEN-mediated NLRP3 dephosphorylation at Tyr 32 is critical for inflammasome activation.
Fig. 6: NLRP3 dephosphorylation at Tyr 32 enables the NLRP3–ASC interaction.
Fig. 7: Myeloid PTEN determines chemotherapy efficiency by activating the NLRP3 inflammasome.
Fig. 8: Myeloid PTEN expression correlates chemotherapy-induced antitumour immunity in patients with cancer.

Data availability

MS data have been deposited in iProX with the primary accession code IPX0001867000. Source data are available online for Figs. 1–8 and Extended Data Figs. 1–8. All other data supporting the findings of this study are available from the corresponding authors on reasonable request.

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Acknowledgements

We thank J. Tschopp and Z. Lian for providing mice lines. This research was supported by the National Key research and development program of China (grant number 2019YFA0508503), the Strategic Priority Research Program of the Chinese Academy of Sciences (grant number XDB29030102), the National Natural Science Foundation of China (grant numbers 31770991, 91742202, 81525013, 81722022, 81788101, 81821001 and 81722037), the Young Talent Support Program and Fundamental Research Funds for the Central Universities and the University Synergy Innovation Program of Anhui Province (GXXT-2019-026).

Author information

Authors and Affiliations

  1. Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Yi Huang, Huanyu Wang, Yize Hao, Hualong Lin, Jin Ye, Huafeng Zhang, Li Bai, Tengchuan Jin, Chao Wang, Wei Jiang & Rongbin Zhou

  2. CAS Centre for Excellence in Cell and Molecular Biology, University of Science and Technology of China, Hefei, China

    Yi Huang & Rongbin Zhou

  3. Wannan Medical College, Wuhu, China

    Menghao Dong

  4. Department of Oncology, the First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Menghao Dong, Benjie Shan & Yueyin Pan

  5. National Center for Protein Sciences (Beijing), State Key Laboratory of Proteomics, Institute of Lifeomics, Beijing, China

    Lei Song

  6. State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China

    Yunzhi Wang & Chen Ding

  7. Suzhou Institute of Systems Medicine, Suzhou, China

    Qingqing Li, Guido Kroemer & Yuting Ma

  8. Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Shanghai Medical College, Key Laboratory of Breast Cancer in Shanghai, Innovation Center for Cell Signaling Network, Cancer Institute, Fudan University, Shanghai, China

    Yizhou Jiang, Zhiming Shao & Suling Liu

  9. Department of Oncology, Department of Breast Surgery, Shanghai Medical College, Fudan University, Shanghai, China

    Yizhou Jiang & Zhiming Shao

  10. Fudan University Zhongshan Hospital, Shanghai Medical College, Shanghai, China

    Hongqi Li

  11. Université Paris Descartes, Sorbonne Paris Cité, Paris, France

    Guido Kroemer

  12. Equipe 11 Labellisée Ligue Nationale Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France

    Guido Kroemer

  13. Institut National de la Santé et de la Recherche Médicale, Paris, France

    Guido Kroemer

  14. Université Pierre et Marie Curie, Paris, France

    Guido Kroemer

  15. Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, France

    Guido Kroemer

  16. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

  17. Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden

    Guido Kroemer

  18. Center for Systems Medicine, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China

    Yuting Ma

  19. Department of Pathology, Anhui Medical University, Hefei, China

    Yongping Cai

Authors
  1. Yi Huang
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  2. Huanyu Wang
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  3. Yize Hao
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  4. Hualong Lin
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  6. Jin Ye
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Contributions

Y. Huang, H.W., Y. Hao and H. Lin performed most of the experiments of this work. M.D., B.S., Y.J. and H. Li collected patient samples. L.S. and Y.W. performed the MS analyses. J.Y. performed the protein purification. Q.L., Z.S., G.K., H.Z., L.B., T.J., C.W., Y.M., Y.C., C.D., S.L., Y.P., W.J. and R.Z. designed the research. Y. Huang, W.J. and R.Z. wrote the manuscript. W.J. and R.Z. supervised the project.

Corresponding authors

Correspondence to Suling Liu, Yueyin Pan, Wei Jiang or Rongbin Zhou.

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Extended data

Extended Data Fig. 1 Myeloid-cell PTEN is necessary for chemotherapy.

a, Immunoblot analysis of PTEN expression in purified tumour-infiltrating macrophages (TIMs). n = 2 biologically independent experiments. b, Immunoblot analysis of PTEN expression in purified peritoneal macrophages. n = 3 biologically independent experiments. c, 5 × 105 MCA205 cells were implanted sub-cutaneously into Ptenf/f or PtenmKO mice. Mitoxantrone were injected intraperitoneally when the size of tumor reached 20-45 mm2. Images of tumors at day 21 after tumor cells implanted. n = 10 biologically independent animals. d-g, 8-week old Ptenf/f or PtenmKO mice were inoculated with 5 × 105 MCA205, TC-1 or 3 × 105 EL-4 tumor cells sub-cutaneously or 3 × 105 PY8119 tumor cells at fourth mammary fat pads. When the size of tumor reached 20–45 mm2 of TC-1 (e), MCA205 (f) and Py8119 (g), or 70-90 mm2 of EL-4 (d), Mitoxantrone (MTX, 5.17 mg/kg), oxaliplatin (OXP, 5 mg/kg) or epirubicin (EPI, 7mg/kg) were injected intraperitoneally as indicated. Tumor size at various times (horizontal axis) after tumor cells injection. n = 5 biologically independent animals. h, i, FACS analysis of CD44 and CD62L expression in CD8+ T cells from tumor tissues after 5-day chemotherapy. n = 5 biologically independent animals. d-g, i, Data are shown as mean ± s.e.m. Statistics were analyzed using two-sided unpaired Student’s t-test. Source data are provided in Source Data Extended Data Fig. 1.

Source data

Extended Data Fig. 2 The tumoricidal activity of mitoxantrone depends on the NLRP3 inflammasome.

a, Immunoblot analysis of NLRP3 expression in purified tumour-infiltrating macrophages (TIMs). n = 2 biologically independent experiments. b, Immunoblot analysis of NLRP3 expression in purified peritoneal macrophages. n = 3 biologically independent experiments. c-f, 5 × 105 MCA205 cells were implanted sub-cutaneously into Nlrp3+/+ or Nlrp3−/− mice. When the size of tumor reached 20-45 mm2, Mitoxantrone were injected intraperitoneally. Survival analysis of Nlrp3+/+ and Nlrp3−/− mice at various times (horizontal axis) after tumor cells injection (c; n = 7 biologically independent animals). Images of tumors at day 21 after tumor cells implanted (d; n = 8 biologically independent animals). Tumor size at various times (horizontal axis) after tumor cells injection (e; n = 8 biologically independent animals). ELISA analysis of IFN-γ secretion of inguinal lymph node cells after 5-day chemotherapy (f; n = 7 biologically independent animals). e, f, Data are shown as mean ± s.e.m. Statistics were analyzed using two-sided log-rank (Mantel–Cox) test (c) or two-sided unpaired Student’s t-test (e, f). Source data are provided in Source Data Extended Data Fig. 2.

Source data

Extended Data Fig. 3 PTEN is required for NLRP3 inflammasome activation.

a, b, PTEN-knockdown THP-1 cells were primed with 200 ng/ml LPS for 3 h and then stimulated with various doses (above lanes) nigericin. Immunoblot analysis of IL-1β and caspase-1 in culture supernatants, and immunoblot analysis of the expression of PTEN, pro-IL-1β and pro-caspase-1 in lysates of those cells (a; n = 2 biologically independent experiments). ELISA analysis of IL-1β in culture supernatants (b; n = 4 biologically independent experiments). c, d, ELISA analysis of TNF-α (c) or IL-6 (d) in culture supernatants of Ptenf/f or PtenmKO BMDMs primed with LPS for 3 h and then stimulated with various doses (above lanes) nigericin. n = 4 biologically independent experiments. e, g, Immunoblot analysis of IL-1β and caspase-1 in culture supernatants of Ptenf/f or PtenmKO BMDMs primed with 50 ng/ml LPS for 3 h and then stimulated with poly A:T (e) or salmonella (g), and immunoblot analysis of pro-IL-1β and pro-caspase-1 in lysates of those cells. n = 2 biologically independent experiments. f, h, ELISA analysis of IL-1β in culture supernatants of Ptenf/f or PtenmKO BMDMs primed with 50 ng/ml LPS for 3 h and then stimulated with poly A:T (f) or salmonella (h). n = 4 biologically independent experiments. i, Immunoblot analysis of the expression of p-AKT, total AKT and PTEN in lysates of those cells of Ptenf/f or PtenmKO BMDMs primed with LPS for 3 h, and then treated with wortmannin (1 µM) or LY294002 (5 µM) for 30 min. n = 2 biologically independent experiments. b-d, f, h, Data are shown as mean ± s.e.m. Statistics were analyzed using two-sided unpaired Student’s t-test. Source data are provided in Source Data Extended Data Fig. 3.

Source data

Extended Data Fig. 4 PTEN has no effects on potassium efflux or mitochondrial damage during NLRP3 activation.

a, Qualification analysis of potassium efflux in Ptenf/f or PtenmKO BMDMs primed with LPS for 3 h, and then stimulated with nigericin for 30 min. Mock groups n = 2 biologically independent experiments, treated groups n = 4 biologically independent experiments. b, Confocal microscopy analysis in Ptenf/f or PtenmKO BMDMs primed with LPS for 3 h, and then stimulated with nigericin for 30 min, followed by staining with Mitosox, Mitotracker red and DAPI. Scale bars, 10 μm. n = 2 biologically independent experiments. c, Commassie blue stainning of recombinant human NLRP3 and PTEN protein. d, e, Scheme of NLRP3 (d) or PTEN (e) domain structure. a, Data are shown mean ± s.e.m. Statistics were analyzed using two-sided unpaired Student’s t-test. Source data are provided in Source Data Extended Data Fig. 4.

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Extended Data Fig. 5 PTEN mediates NLRP3 dephosphorylation at Y32 is required for inflammasome activation.

a, Extracted ion chromatograms (XIC) of the peptide phosphorylated at Tyr32 (MHLEDpYPPQKGCIPLPR), Thr193 (pTKTCESPVSPIK) and Thr 195 (pTCESPVSPIK) of NLRP3 with or without PTEN overexpression. b, Multiple sequence alignment of NLRP3 from the indicated species. c, d, Immunoblot analysis of IL-1β and caspase-1 (c; n = 2 biologically independent experiments.) or ELISA analysis of IL-1β (d; n = 4 biologically independent experiments) in culture supernatants of Ptenf/fNlrp3−/− or PtenmKONlrp3−/− BMDMs transduced with mouse WT or mutant pLEX-NLRP3 lentivirus, and then primed with LPS, stimulated with nigericin. e, Immunoblot analysis of the immunoprecipitated Flag-tagged WT or nonphosphorylatable mutants (Y30A) NLRP3 with mouse NLRP3 specific phospho-Tyr30 antibody (p-NLRP3). n = 2 biologically independent experiments. f, Immunoblot analysis of the immunoprecipitated Flag-tagged NLRP3 with p-NLRP3 antibody when NLRP3 were coexpressed with PTEN. n = 2 biologically independent experiments. g, Commassie blue stainning of recombinant mouse NLRP3 and PTEN, PTEN mutant C124S, G129E or G129R protein. d, Data are shown as mean ± s.e.m. Statistics were analyzed using two-sided unpaired Student’s t-test. Source data are provided in Source Data Extended Data Fig. 5.

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Extended Data Fig. 6 Construction of Nlrp3Y30E/Y30E mice.

a, Nlrp3Y30E/Y30E mice was generated using CRISPR/Cas9-mediated genome editing. The sequence of guide RNA (gRNA) binding site on the homologous DNA sequence had indicated. b, Nlrp3Y30E/Y30E mice was validated by DNA sequencing.

Extended Data Fig. 7 Myeloid PTEN determines chemotherapy-induced antitumor immunity through activating NLRP3 inflammasome.

a–c, 5 × 105 MCA205 cells were implanted sub-cutaneously into Nlrp3+/+ or Nlrp3Y30E/Y30E mice. Mitoxantrone were injected intraperitoneally when the size of tumor reached 20-45 mm2. Images of tumors at day 21 after tumor cells implanted (a; n = 6 biologically independent animals). FACS analysis of intracellular IFN-γ in CD8+ T cells from inguinal lymph nodes after 5-day chemotherapy (b, c; n = 4 biologically independent animals). d-f, 5 × 105 MCA205 cells were implanted sub-cutaneously into Ptenf/fNlrp3+/+, PtenmKONlrp3+/+, Ptenf/fNlrp3−/− or PtenmKONlrp3−/− mice. Mitoxantrone were injected intraperitoneally when the size of tumor reached 20-45 mm2. Images of tumors at day 21 after tumor cells implanted (d; n = 5 biologically independent animals). FACS analysis of intracellular IFN-γ in CD8+ T cells from inguinal lymph nodes after 5-day chemotherapy (e, f; n = 4 biologically independent animals). c, f, Data are shown as mean ± s.e.m. Statistics were analyzed using two-sided unpaired Student’s t-test. Source data are provided in Source Data Extended Data Fig. 7.

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Extended Data Fig. 8 Myeloid PTEN correlates chemotherapy-induced antitumor immunity in human cancer patients.

a, Kaplan–Meier curve analysis of the overall survival probabilities of patients with breast cancer influenced by PTEN expression. Ptenlow groups n = 177 biologically independent patients, Ptenhigh groups n = 449 biologically independent patients. b-d, Correlations analysis between the MOD of PTEN in tumor cells with IL-1β concentrations in serum (b), CD8α (c) or IFNG (d) mRNA expression in tumor tissues from cohort 1. n = 32 biologically independent patients. e, Correlations analysis between the MOD of PTEN in tumor cells and IL-1β concentrations in serum from cohort 2. n = 34 biologically independent patients. Statistics were analyzed using two-sided log-rank (Mantel–Cox) test (a) or two-sided unpaired Student’s t-test (b-e). Source data are provided in Source Data Extended Data Fig. 8.

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Supplementary information

Supplementary Information

Supplementary Fig. 1

Reporting Summary

Supplementary Tables 1–4

Supplementary Table 1: phosphorylation sites analyses of NLRP3 by MS. Supplementary Table 2: MS identification the change of NLRP3 phosphorylation with or without PTEN overexpression. Supplementary Table 3: summary of information about the patients with breast cancer who have been treated with AAC (cohort 1). Supplementary Table 4: summary of information about patients with breast cancer before they were treated with AAC (cohort 2).

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Huang, Y., Wang, H., Hao, Y. et al. Myeloid PTEN promotes chemotherapy-induced NLRP3-inflammasome activation and antitumour immunity. Nat Cell Biol 22, 716–727 (2020). https://doi.org/10.1038/s41556-020-0510-3

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