Autophagy induction by thiostrepton improves the efficacy of immunogenic chemotherapy.
Animals
Anti-Bacterial Agents
/ pharmacology
Antineoplastic Agents
/ pharmacology
Autophagy
/ drug effects
Calreticulin
/ metabolism
Cell Line, Tumor
Disease Models, Animal
Female
HMGB1 Protein
/ metabolism
Humans
Immunogenic Cell Death
Mice
Mice, Inbred C57BL
Neoplasms
/ drug therapy
Oxaliplatin
/ pharmacology
T-Lymphocytes, Cytotoxic
/ drug effects
Thiostrepton
/ pharmacology
adaptive immunity
immunomodulation
Journal
Journal for immunotherapy of cancer
ISSN: 2051-1426
Titre abrégé: J Immunother Cancer
Pays: England
ID NLM: 101620585
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
accepted:
11
03
2020
entrez:
30
3
2020
pubmed:
30
3
2020
medline:
11
11
2020
Statut:
ppublish
Résumé
Immunogenic cell death (ICD) is a peculiar modality of cellular demise that elicits adaptive immune responses and triggers T cell-dependent immunity. Fluorescent biosensors were employed for an unbiased drug screen approach aiming at the identification of ICD enhancers. Here, we discovered thiostrepton as an enhancer of ICD able to boost chemotherapy-induced ATP release, calreticulin exposure and high-mobility group box 1 exodus. Moreover, thiostrepton enhanced anticancer immune responses of oxaliplatin (OXA) in vivo in immunocompetent mice, yet failed to do so in immunodeficient animals. Consistently, thiostrepton combined with OXA altered the ratio of cytotoxic T lymphocytes to regulatory T cells, thus overcoming immunosuppression and reinstating anticancer immunosurveillance. Altogether, these results indicate that thiostrepton can be advantageously combined with chemotherapy to enhance anticancer immunogenicity.
Sections du résumé
BACKGROUND
Immunogenic cell death (ICD) is a peculiar modality of cellular demise that elicits adaptive immune responses and triggers T cell-dependent immunity.
METHODS
Fluorescent biosensors were employed for an unbiased drug screen approach aiming at the identification of ICD enhancers.
RESULTS
Here, we discovered thiostrepton as an enhancer of ICD able to boost chemotherapy-induced ATP release, calreticulin exposure and high-mobility group box 1 exodus. Moreover, thiostrepton enhanced anticancer immune responses of oxaliplatin (OXA) in vivo in immunocompetent mice, yet failed to do so in immunodeficient animals. Consistently, thiostrepton combined with OXA altered the ratio of cytotoxic T lymphocytes to regulatory T cells, thus overcoming immunosuppression and reinstating anticancer immunosurveillance.
CONCLUSION
Altogether, these results indicate that thiostrepton can be advantageously combined with chemotherapy to enhance anticancer immunogenicity.
Identifiants
pubmed: 32221018
pii: jitc-2019-000462
doi: 10.1136/jitc-2019-000462
pmc: PMC7206967
pii:
doi:
Substances chimiques
Anti-Bacterial Agents
0
Antineoplastic Agents
0
CALR protein, human
0
Calreticulin
0
HMGB1 Protein
0
Oxaliplatin
04ZR38536J
Thiostrepton
HR4S203Y18
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: OK and GK are scientific co-founders of Samsara Therapeutics.
Références
Antibiot Annu. 1955-1956;3:560-1
pubmed: 13355326
Int J Dev Biol. 2015;59(1-3):131-40
pubmed: 26374534
Science. 2018 Mar 23;359(6382):1366-1370
pubmed: 29567708
Oncoimmunology. 2019 Sep 27;8(12):e1667743
pubmed: 31741770
Oncoimmunology. 2018 Aug 1;7(9):e1462431
pubmed: 30228932
Nat Rev Immunol. 2017 Feb;17(2):97-111
pubmed: 27748397
Oncogene. 2010 Jan 28;29(4):482-91
pubmed: 19881547
Mol Cancer Res. 2010 Jan;8(1):24-34
pubmed: 20068070
Nat Commun. 2019 Apr 2;10(1):1486
pubmed: 30940805
Antibiot Annu. 1955-1956;3:562-5
pubmed: 13355327
Nat Med. 2007 Jan;13(1):54-61
pubmed: 17187072
Semin Cancer Biol. 2015 Aug;33:86-92
pubmed: 25749194
Antibiot Annu. 1955-1956;3:554-9
pubmed: 13355325
Oncoimmunology. 2019 Apr 12;8(7):1596005
pubmed: 31143518
Nat Med. 2009 Oct;15(10):1170-8
pubmed: 19767732
Genes Immun. 2019 Jul;20(6):509-513
pubmed: 30282994
J Med Genet. 1999 Oct;36(10):739-46
pubmed: 10528852
EBioMedicine. 2018 Apr;30:261-272
pubmed: 29606629
Autophagy. 2019 Sep;15(9):1662-1664
pubmed: 31248332
J Biol Chem. 2007 Aug 17;282(33):24131-45
pubmed: 17580304
Autophagy. 2007 Sep-Oct;3(5):452-60
pubmed: 17534139
Nat Med. 2007 Sep;13(9):1050-9
pubmed: 17704786
Hum Mol Genet. 2002 May 1;11(9):1107-17
pubmed: 11978769
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):190-5
pubmed: 11756670
Immunity. 2016 Feb 16;44(2):343-54
pubmed: 26872698
Science. 2013 Nov 22;342(6161):971-6
pubmed: 24264990
Oncoimmunology. 2017 Oct 4;6(12):e1386829
pubmed: 29209573
Vet Med Small Anim Clin. 1981 Apr;76(4):535-8
pubmed: 6908773
Cell. 2005 Oct 21;123(2):321-34
pubmed: 16239148
Science. 2018 Jan 5;359(6371):91-97
pubmed: 29097494
Carcinogenesis. 2000 Mar;21(3):485-95
pubmed: 10688869
EMBO Mol Med. 2019 Nov 7;11(11):e10469
pubmed: 31609086
Cell Death Differ. 2018 Aug;25(8):1375-1393
pubmed: 29358668
Immunol Rev. 2017 Nov;280(1):74-82
pubmed: 29027228
Oncoimmunology. 2019 Jul 22;8(10):e1637188
pubmed: 31646079
Sci Transl Med. 2012 Jul 18;4(143):143ra99
pubmed: 22814852
Eur J Biochem. 1976 Nov 1;70(1):39-47
pubmed: 795651
Nat Commun. 2019 Jul 26;10(1):3349
pubmed: 31350406
Science. 2013 Nov 22;342(6161):967-70
pubmed: 24264989
Oncoimmunology. 2018 May 31;7(8):e1466765
pubmed: 30221067