Heat shock and HSP70 regulate 5-FU-mediated caspase-1 activation in myeloid-derived suppressor cells and tumor growth in mice
Open Access
- 1 January 2020
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 8 (1), e000478
- https://doi.org/10.1136/jitc-2019-000478
Abstract
Background We have previously shown that 5-fluorouracil (5-FU) selectively kills myeloid-derived suppressor cells (MDSCs) and activates NLRP3 (NOD-leucine rich repeat and pyrin containing protein 3) inflammasome. NLRP3 activation leads to caspase-1 activation and production of IL-1 beta, which in turn favors secondary tumor growth. We decided to explore the effects of either a heat shock (HS) or the deficiency in heat shock protein (HSP) 70, previously shown to respectively inhibit or increase NLRP3 inflammasome activation in macrophages. Methods Caspase-1 activation was detected in vitro in MSC-2 cells by western blot and in vivo or ex vivo in tumor and/or splenic MDSCs by flow cytometry. The effects of HS, HSP70 deficiency and anakinra (an IL-1 inhibitor) on tumor growth and mice survival were studied in C57BL/6 WT orHsp70(-/-)tumor-bearing mice. Finally, Th17 polarization was evaluated by qPCR (Il17a, Rorc) and angiogenic markers by qPCR (Pecam1, Eng) and immunohistochemistry (ERG). Results HS inhibits 5-FU-mediated caspase-1 activation in vitro and in vivo without affecting its cytotoxicity on MDSCs. Moreover, it enhances the antitumor effect of 5-FU treatment and favors mice survival. Interestingly, it is associated to a decreased Th17 and angiogenesis markers in tumors. IL-1 beta injection is able to bypass HS+5-FU antitumor effects. In contrast, inHsp70(-/-)MDSCs, 5-FU-mediated caspase-1 activation is increased in vivo and in vitro without effect on 5-FU cytotoxicity. InHsp70(-/-)mice, the antitumor effect of 5-FU was impeded, with an increased Th17 and angiogenesis markers in tumors. Finally, the effects of 5-FU on tumor growth can be restored by inhibiting IL-1 beta, using anakinra. Conclusion This study provides evidence on the role of HSP70 in tuning 5-FU antitumor effect and suggests that HS can be used to improve 5-FU anticancer effect.Keywords
Funding Information
- Labex
- ARC
This publication has 24 references indexed in Scilit:
- Cadmium Modifies the Cell Cycle and Apoptotic Profiles of Human Breast Cancer Cells Treated with 5-FluorouracilInternational Journal of Molecular Sciences, 2013
- Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasomeNature Immunology, 2013
- Functions of NOD-Like Receptors in Human DiseasesFrontiers in Immunology, 2013
- Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growthNature Medicine, 2012
- 5-Fluorouracil Selectively Kills Tumor-Associated Myeloid-Derived Suppressor Cells Resulting in Enhanced T Cell–Dependent Antitumor ImmunityCancer Research, 2010
- Hyperthermia dose-effect relationship in 420 patients with cervical cancer treated with combined radiotherapy and hyperthermiaEuropean Journal Of Cancer, 2009
- Hyperthermia as an adjunctive treatment for soft-tissue sarcomaExpert Review of Anticancer Therapy, 2009
- Polymorphism of the heat-shock protein gene Hsp70-2, but not polymorphisms of the IL-10 and CD14 genes, is associated with the outcome of Crohn's diseaseScandinavian Journal of Gastroenterology, 2005
- Hyperthermia as an adjuvant to radiation therapy of recurrent or metastatic malignant melanoma. A multicentre randomized trial by the European Society for Hyperthermic OncologyInternational Journal of Hyperthermia, 1996
- POLYMORPHISM OF THE HEAT-SHOCK PROTEIN GENE HSP70-2IN SYSTEMIC LUPUS ERYTHEMATOSUSRheumatology, 1995