Chemotherapy-triggered Cathepsin B Release in Myeloid-derived Suppressor Cells Activates the Nlrp3 Inflammasome and Promotes Tumor Growth

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2012 Dec 4

PMID 23202296

Citations 395

Authors

Melanie Bruchard

Gregoire Mignot

Valentin Derangere

Fanny Chalmin

Angelique Chevriaux

Frederique Vegran

Wilfrid Boireau

Benoit Simon

Bernhard Ryffel

Jean Louis Connat

Jean Kanellopoulos

Francois Martin

Cedric Rebe

Lionel Apetoh

Francois Ghiringhelli

Affiliations

Soon will be listed here.

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.

Citing Articles

Inflammation in cancer: therapeutic opportunities from new insights.

Xie Y, Liu F, Wu Y, Zhu Y, Jiang Y, Wu Q Mol Cancer. 2025; 24(1):51.

PMID: 39994787 PMC: 11849313. DOI: 10.1186/s12943-025-02243-8.

Conventional Chemotherapy and Inflammation: What Is the Role of the Inflammasome in the Tumor Microenvironment?.

Colarusso C, Terlizzi M, Di Caprio S, Falanga A, DAndria E, dEmmanuele di Villa Bianca R Biomedicines. 2025; 13(1).

PMID: 39857785 PMC: 11762891. DOI: 10.3390/biomedicines13010203.

Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance.

Zhao P, Yin S, Qiu Y, Sun C, Yu H Mol Cancer. 2025; 24(1):23.

PMID: 39825385 PMC: 11740669. DOI: 10.1186/s12943-024-02217-2.

Safety and efficacy of trifluridine/tipiracil +/- bevacizumab plus XB2001 (anti-IL-1α antibody): a single-center phase 1 trial.

Thibaudin M, Roussot N, Burlot C, Schmitt A, Vincent J, Tharin Z Signal Transduct Target Ther. 2025; 10(1):22.

PMID: 39820336 PMC: 11739593. DOI: 10.1038/s41392-024-02116-4.

Cytokine-armed pyroptosis induces antitumor immunity against diverse types of tumors.

Orehek S, Ramuta T, Lainscek D, Malensek S, Sala M, Bencina M Nat Commun. 2024; 15(1):10801.

PMID: 39737979 PMC: 11686184. DOI: 10.1038/s41467-024-55083-3.

References

Numasaki M, Fukushi J, Ono M, Narula S, Zavodny P, Kudo T . Interleukin-17 promotes angiogenesis and tumor growth. Blood. 2002; 101(7):2620-7. DOI: 10.1182/blood-2002-05-1461. View

Nagaraj S, Gabrilovich D . Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res. 2008; 68(8):2561-3. DOI: 10.1158/0008-5472.CAN-07-6229. View

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. 2011; 11(5):365-72. DOI: 10.2174/156652411795976574. View

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. 2008; 24(5):1121-7. DOI: 10.1016/j.bios.2008.06.030. View

Tschopp J, Martinon F, Burns K . NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol. 2003; 4(2):95-104. DOI: 10.1038/nrm1019. View

Menard 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. 2008; 57(11):1579-87. PMC: 11030219. DOI: 10.1007/s00262-008-0505-6. View

Ostrand-Rosenberg S, Sinha P . Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009; 182(8):4499-506. PMC: 2810498. DOI: 10.4049/jimmunol.0802740. View

Mini E, Nobili S, Caciagli B, Landini I, Mazzei T . Cellular pharmacology of gemcitabine. Ann Oncol. 2006; 17 Suppl 5:v7-12. DOI: 10.1093/annonc/mdj941. View

Chung Y, Chang S, Martinez G, Yang X, Nurieva R, Kang H . Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity. 2009; 30(4):576-87. PMC: 2705871. DOI: 10.1016/j.immuni.2009.02.007. View

10.

Grivennikov S, Greten F, Karin M . Immunity, inflammation, and cancer. Cell. 2010; 140(6):883-99. PMC: 2866629. DOI: 10.1016/j.cell.2010.01.025. View

11.

Buttle D, Murata M, Knight C, Barrett A . CA074 methyl ester: a proinhibitor for intracellular cathepsin B. Arch Biochem Biophys. 1992; 299(2):377-80. DOI: 10.1016/0003-9861(92)90290-d. View

12.

Hagemann T, Balkwill F, Lawrence T . Inflammation and cancer: a double-edged sword. Cancer Cell. 2007; 12(4):300-1. PMC: 2592547. DOI: 10.1016/j.ccr.2007.10.005. View

13.

Zitvogel L, Apetoh L, Ghiringhelli F, Kroemer G . Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2007; 8(1):59-73. DOI: 10.1038/nri2216. View

14.

Obeid M, Tesniere A, Ghiringhelli F, Fimia G, Apetoh L, Perfettini J . Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2006; 13(1):54-61. DOI: 10.1038/nm1523. View

15.

Greten F, Eckmann L, Greten T, Park J, Li Z, Egan L . IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004; 118(3):285-96. DOI: 10.1016/j.cell.2004.07.013. View

16.

Gross O, Thomas C, Guarda G, Tschopp J . The inflammasome: an integrated view. Immunol Rev. 2011; 243(1):136-51. DOI: 10.1111/j.1600-065X.2011.01046.x. View

17.

Bunt S, Yang L, Sinha P, Clements V, Leips J, Ostrand-Rosenberg S . Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res. 2007; 67(20):10019-26. PMC: 4402704. DOI: 10.1158/0008-5472.CAN-07-2354. View

18.

Wang L, Yi T, Kortylewski M, Pardoll D, Zeng D, Yu H . IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009; 206(7):1457-64. PMC: 2715087. DOI: 10.1084/jem.20090207. View

19.

Michaud M, Martins I, Sukkurwala A, Adjemian S, Ma Y, Pellegatti P . Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science. 2011; 334(6062):1573-7. DOI: 10.1126/science.1208347. View

20.

Zhang L, Conejo-Garcia J, Katsaros D, Gimotty P, Massobrio M, Regnani G . Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003; 348(3):203-13. DOI: 10.1056/NEJMoa020177. View