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Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth

Nature Medicine volume 19, pages 57–64 (2013)Cite this article

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Abstract

Chemotherapeutic agents are widely used for cancer treatment. In addition to their direct cytotoxic effects, these agents harness the host's immune system, which contributes to their antitumor activity. Here we show that two clinically used chemotherapeutic agents, gemcitabine (Gem) and 5-fluorouracil (5FU), activate the NOD-like receptor family, pyrin domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. Chemotherapy-triggered IL-1β secretion relied on lysosomal permeabilization and the release of cathepsin B, which bound to Nlrp3 and drove caspase-1 activation. MDSC-derived IL-1β induced secretion of IL-17 by CD4+ T cells, which blunted the anticancer efficacy of the chemotherapy. Accordingly, Gem and 5FU exerted higher antitumor effects when tumors were established in Nlrp3−/− or Casp1−/− mice or wild-type mice treated with interleukin-1 receptor antagonist (IL-1Ra). Altogether, these results identify how activation of the Nlrp3 inflammasome in MDSCs by 5FU and Gem limits the antitumor efficacy of these chemotherapeutic agents.

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Figure 1: 5FU and Gem activate caspase-1 in MDSCs.
Figure 2: 5FU and Gem promote the secretion of bioactive IL-1β in a NLRP3-dependent manner.
Figure 3: 5FU- and Gem-induced NLRP3 inflammasome activation results from cathepsin B release from lysosomes.
Figure 4: Nlrp3 binds to cathepsin B.
Figure 5: NLRP3-dependent IL-1β production restrains the antitumor effect of 5FU.
Figure 6: NLRP3-dependent IL-1β production enhances IL-17 production by CD4+ T cells that restrain the antitumor effect of 5FU.

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References

  1. Pagès, F. et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N. Engl. J. Med. 353, 2654–2666 (2005).

    PubMed  Google Scholar 

  2. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).

    CAS  PubMed  Google Scholar 

  3. Mattarollo, S.R. et al. Pivotal role of innate and adaptive immunity in anthracycline chemotherapy of established tumors. Cancer Res. 71, 4809–4820 (2011).

    CAS  PubMed  Google Scholar 

  4. Ménard, C., Martin, F., Apetoh, L., Bouyer, F. & Ghiringhelli, F. Cancer chemotherapy: not only a direct cytotoxic effect, but also an adjuvant for antitumor immunity. Cancer Immunol. Immunother. 57, 1579–1587 (2008).

    PubMed  Google Scholar 

  5. Ghiringhelli, F. et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1β–dependent adaptive immunity against tumors. Nat. Med. 15, 1170–1178 (2009).

    CAS  PubMed  Google Scholar 

  6. Sinha, P., Clements, V.K., Bunt, S.K., Albelda, S.M. & Ostrand-Rosenberg, S. Cross-talk between myeloid-derived suppressor cells and macrophages subverts tumor immunity toward a type 2 response. J. Immunol. 179, 977–983 (2007).

    CAS  PubMed  Google Scholar 

  7. Le, H.K. et al. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int. Immunopharmacol. 9, 900–909 (2009).

    CAS  PubMed  Google Scholar 

  8. Mundy-Bosse, B.L. et al. Myeloid-derived suppressor cell inhibition of the IFN response in tumor-bearing mice. Cancer Res. 71, 5101–5110 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Vincent, J. et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell–dependent antitumor immunity. Cancer Res. 70, 3052–3061 (2010).

    CAS  PubMed  Google Scholar 

  10. Suzuki, E., Kapoor, V., Jassar, A.S., Kaiser, L.R. & Albelda, S.M. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin. Cancer Res. 11, 6713–6721 (2005).

    CAS  PubMed  Google Scholar 

  11. Apetoh, L., Vegran, F., Ladoire, S. & Ghiringhelli, F. Restoration of antitumor immunity through selective inhibition of myeloid derived suppressor cells by anticancer therapies. Curr. Mol. Med. 11, 365–372 (2011).

    CAS  PubMed  Google Scholar 

  12. Ostrand-Rosenberg, S. & Sinha, P. Myeloid-derived suppressor cells: linking inflammation and cancer. J. Immunol. 182, 4499–4506 (2009).

    CAS  PubMed  Google Scholar 

  13. Gabrilovich, D.I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Nagaraj, S. & Gabrilovich, D.I. Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res. 68, 2561–2563 (2008).

    CAS  PubMed  Google Scholar 

  15. Longley, D.B., Harkin, D.P. & Johnston, P.G. 5-fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer 3, 330–338 (2003).

    CAS  PubMed  Google Scholar 

  16. Mini, E., Nobili, S., Caciagli, B., Landini, I. & Mazzei, T. Cellular pharmacology of gemcitabine. Ann. Oncol. 17 (suppl. 5), v7–v12 (2006).

    PubMed  Google Scholar 

  17. Gross, O., Thomas, C.J., Guarda, G. & Tschopp, J. The inflammasome: an integrated view. Immunol. Rev. 243, 136–151 (2011).

    CAS  PubMed  Google Scholar 

  18. Pétrilli, V., Dostert, C., Muruve, D.A. & Tschopp, J. The inflammasome: a danger sensing complex triggering innate immunity. Curr. Opin. Immunol. 19, 615–622 (2007).

    PubMed  Google Scholar 

  19. Buttle, D.J., Murata, M., Knight, C.G. & Barrett, A.J. CA074 methyl ester: a proinhibitor for intracellular cathepsin B. Arch. Biochem. Biophys. 299, 377–380 (1992).

    CAS  PubMed  Google Scholar 

  20. Tschopp, J., Martinon, F. & Burns, K. NALPs: a novel protein family involved in inflammation. Nat. Rev. Mol. Cell Biol. 4, 95–104 (2003).

    CAS  PubMed  Google Scholar 

  21. Dinarello, C.A. Why not treat human cancer with interleukin-1 blockade? Cancer Metastasis Rev. 29, 317–329 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Acosta-Rodriguez, E.V., Napolitani, G., Lanzavecchia, A. & Sallusto, F. Interleukins 1β and 6 but not transforming growth factor-β are essential for the differentiation of interleukin 17–producing human T helper cells. Nat. Immunol. 8, 942–949 (2007).

    CAS  PubMed  Google Scholar 

  23. Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576–587 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Qin, H. et al. TGF-β promotes Th17 cell development through inhibition of SOCS3. J. Immunol. 183, 97–105 (2009).

    CAS  PubMed  Google Scholar 

  25. He, D. et al. IL-17 promotes tumor development through the induction of tumor promoting microenvironments at tumor sites and myeloid-derived suppressor cells. J. Immunol. 184, 2281–2288 (2010).

    CAS  PubMed  Google Scholar 

  26. Kujawski, M. et al. Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice. J. Clin. Invest. 118, 3367–3377 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang, C. & Youle, R.J. Predominant requirement of Bax for apoptosis in HCT116 cells is determined by Mcl-1's inhibitory effect on Bak. Oncogene 31, 3177–3189 (2012).

    CAS  PubMed  Google Scholar 

  28. Carmi, Y. et al. Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis. J. Immunol. 186, 3462–3471 (2011).

    CAS  PubMed  Google Scholar 

  29. Apte, R.N. & Voronov, E. Is interleukin-1 a good or bad 'guy' in tumor immunobiology and immunotherapy? Immunol. Rev. 222, 222–241 (2008).

    CAS  PubMed  Google Scholar 

  30. Grivennikov, S.I., Greten, F.R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Li, N., Grivennikov, S.I. & Karin, M. The unholy trinity: inflammation, cytokines, and STAT3 shape the cancer microenvironment. Cancer Cell 19, 429–431 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Krelin, Y. et al. Interleukin-1β–driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. Cancer Res. 67, 1062–1071 (2007).

    CAS  PubMed  Google Scholar 

  33. Hagemann, T., Balkwill, F. & Lawrence, T. Inflammation and cancer: a double-edged sword. Cancer Cell 12, 300–301 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Greten, F.R. et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118, 285–296 (2004).

    CAS  PubMed  Google Scholar 

  35. Naugler, W.E. et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317, 121–124 (2007).

    CAS  PubMed  Google Scholar 

  36. Balkwill, F., Charles, K.A. & Mantovani, A. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer Cell 7, 211–217 (2005).

    CAS  PubMed  Google Scholar 

  37. Bunt, S.K. et al. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 67, 10019–10026 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. van Deventer, H.W. et al. The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells. Cancer Res. 70, 10161–10169 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang, L. et al. IL-17 can promote tumor growth through an IL-6–Stat3 signaling pathway. J. Exp. Med. 206, 1457–1464 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Numasaki, M. et al. Interleukin-17 promotes angiogenesis and tumor growth. Blood 101, 2620–2627 (2003).

    CAS  PubMed  Google Scholar 

  41. Zitvogel, L., Apetoh, L., Ghiringhelli, F. & Kroemer, G. Immunological aspects of cancer chemotherapy. Nat. Rev. Immunol. 8, 59–73 (2008).

    CAS  PubMed  Google Scholar 

  42. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    CAS  PubMed  Google Scholar 

  43. Apetoh, L. et al. Toll-like receptor 4–dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).

    CAS  PubMed  Google Scholar 

  44. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).

    CAS  PubMed  Google Scholar 

  45. Boireau, W., Rouleau, A., Lucchi, G. & Ducoroy, P. Revisited BIA-MS combination: entire “on-a-chip” processing leading to the proteins identification at low femtomole to sub-femtomole levels. Biosens. Bioelectron. 24, 1121–1127 (2009).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors of this work are supported by the Fondation pour la Recherche Médicale (FRM) (F.G.), the Association pour le Recherche Contre le Cancer (ARC) (F.G., G.M. and M.B.), the Ligue Nationale Contre le Cancer (F.V.), the Institut National du Cancer (INCa) (F.G.), the Ligue Régionale Contre le Cancer Comité Grand-Est (F.G., C.R. and L.A.), the Fondation de France (F.G.), the Agence Nationale de la Recherche (ANR, ANR-10-PDOC-014-01) (L.A.), the European Commission (Marie Curie Fellowship PCIG10-GA-2011-303719) (L.A.), the Ministère de l'Enseignement Supérieur et de la Recherche (M.B.), INSERM and Région Bourgogne (F.C.) and LabEx ANR-11-LABX-0021. We thank P. Schneider (Biochemistry Department, Université de Lausanne), V. Bronte (Istituto Oncologico, Padova, Italy) and T. Reinheckel (Institute of Molecular Medicine and Cell Research Freiburg, Germany) for providing essential material.

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Author notes

  1. Mélanie Bruchard, Grégoire Mignot, Lionel Apetoh and François Ghiringhelli: These authors contributed equally to this work.

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM) U866, Dijon, France

    Mélanie Bruchard, Grégoire Mignot, Valentin Derangère, Fanny Chalmin, Angélique Chevriaux, Frédérique Végran, François Martin, Cédric Rébé, Lionel Apetoh & François Ghiringhelli

  2. Faculté de Médecine et pharmacie, Université de Bourgogne, Dijon, France

    Mélanie Bruchard, Grégoire Mignot, Valentin Derangère, Fanny Chalmin, Angélique Chevriaux, Frédérique Végran, François Martin, Cédric Rébé, Lionel Apetoh & François Ghiringhelli

  3. Centre Georges François Leclerc, Dijon, France

    Angélique Chevriaux, Cédric Rébé, Lionel Apetoh & François Ghiringhelli

  4. Franche-Comté Electronique, Mécanique, Thermique et Optique–Sciences et Technologies (FEMTO-ST) Institute, Université de Franche Comté, Besançon, France

    Wilfrid Boireau & Benoit Simon

  5. Laboratory of Molecular Immunology and Embryology, Centre National de la Recherche Scientifique (CNRS) Unités Mixtes de Recherche (UMR) 6218, Orléans, France

    Bernhard Ryffel

  6. INSERM U866, Laboratoire de Physiopathologie et Pharmacologie Cardiovasculaires Expérimentales, Institut Fédérative de Recherche (IFR) Santé–Sciences et Techniques de l′Information et de la Communication (STIC), Faculté de Médecine, Université de Bourgogne, Dijon, France

    Jean Louis Connat

  7. UMR 8619, Université Paris Sud-Paris 11, Orsay Cedex, France.,

    Jean Kanellopoulos

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Contributions

M.B., G.M., V.D., F.C., A.C., F.V., W.B., B.S. and C.R. performed in vitro experiments. M.B. and L.A. performed in vivo experiments. B.R., J.L.C. and J.K. provided essential materials. M.B., G.M., L.A., F.M. and F.G. designed the study and analyzed results. M.B., L.A. and F.G. wrote the paper.

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Correspondence to François Ghiringhelli.

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Bruchard, M., Mignot, G., Derangère, V. et al. Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth. Nat Med 19, 57–64 (2013). https://doi.org/10.1038/nm.2999

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