Extracellular HMGB1 blockade inhibits tumor growth through profoundly remodeling immune microenvironment and enhances checkpoint inhibitor-based immunotherapy.
Adaptive Immunity
/ drug effects
Animals
Antineoplastic Combined Chemotherapy Protocols
/ pharmacology
Breast Neoplasms
/ drug therapy
Carcinoma, Non-Small-Cell Lung
/ drug therapy
Cell Line, Tumor
Female
Glycyrrhizic Acid
/ pharmacology
HMGB1 Protein
/ antagonists & inhibitors
Humans
Immune Checkpoint Inhibitors
/ pharmacology
Lung Neoplasms
/ drug therapy
Macrophages
/ drug effects
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Nude
Peptide Fragments
/ pharmacology
RAW 264.7 Cells
S100 Proteins
/ pharmacology
Signal Transduction
Tumor Burden
/ drug effects
Tumor Microenvironment
/ immunology
Uterine Cervical Neoplasms
/ drug therapy
breast neoplasms
translational medical research
tumor microenvironment
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 2021
03 2021
Historique:
accepted:
10
02
2021
entrez:
13
3
2021
pubmed:
14
3
2021
medline:
18
12
2021
Statut:
ppublish
Résumé
High-mobility group box 1 (HMGB1) is a multifunctional redox-sensitive protein involved in various intracellular (eg, chromatin remodeling, transcription, autophagy) and extracellular (inflammation, autoimmunity) processes. Regarding its role in cancer development/progression, paradoxical results exist in the literature and it is still unclear whether HMGB1 mainly acts as an oncogene or a tumor suppressor. HMGB1 expression was first assessed in tissue specimens (n=359) of invasive breast, lung and cervical cancer and the two distinct staining patterns detected (nuclear vs cytoplasmic) were correlated to the secretion profile of malignant cells, patient outcomes and the presence of infiltrating immune cells within tumor microenvironment. Using several orthotopic, syngeneic mouse models of basal-like breast (4T1, 67NR and EpRas) or non-small cell lung (TC-1) cancer, the efficacy of several HMGB1 inhibitors alone and in combination with immune checkpoint blockade antibodies (anti-PD-1/PD-L1) was then investigated. Isolated from retrieved tumors, 14 immune cell (sub)populations as well as the activation status of antigen-presenting cells were extensively analyzed in each condition. Finally, the redox state of HMGB1 in tumor-extruded fluids and the influence of different forms (oxidized, reduced or disulfide) on both dendritic cell (DC) and plasmacytoid DC (pDC) activation were determined. Associated with an unfavorable prognosis in human patients, we clearly demonstrated that targeting extracellular HMGB1 elicits a profound remodeling of tumor immune microenvironment for efficient cancer therapy. Indeed, without affecting the global number of (CD45 Collectively, we present evidence that extracellular HMGB1 blockade may complement first-generation cancer immunotherapies by remobilizing antitumor immune response.
Sections du résumé
BACKGROUND
High-mobility group box 1 (HMGB1) is a multifunctional redox-sensitive protein involved in various intracellular (eg, chromatin remodeling, transcription, autophagy) and extracellular (inflammation, autoimmunity) processes. Regarding its role in cancer development/progression, paradoxical results exist in the literature and it is still unclear whether HMGB1 mainly acts as an oncogene or a tumor suppressor.
METHODS
HMGB1 expression was first assessed in tissue specimens (n=359) of invasive breast, lung and cervical cancer and the two distinct staining patterns detected (nuclear vs cytoplasmic) were correlated to the secretion profile of malignant cells, patient outcomes and the presence of infiltrating immune cells within tumor microenvironment. Using several orthotopic, syngeneic mouse models of basal-like breast (4T1, 67NR and EpRas) or non-small cell lung (TC-1) cancer, the efficacy of several HMGB1 inhibitors alone and in combination with immune checkpoint blockade antibodies (anti-PD-1/PD-L1) was then investigated. Isolated from retrieved tumors, 14 immune cell (sub)populations as well as the activation status of antigen-presenting cells were extensively analyzed in each condition. Finally, the redox state of HMGB1 in tumor-extruded fluids and the influence of different forms (oxidized, reduced or disulfide) on both dendritic cell (DC) and plasmacytoid DC (pDC) activation were determined.
RESULTS
Associated with an unfavorable prognosis in human patients, we clearly demonstrated that targeting extracellular HMGB1 elicits a profound remodeling of tumor immune microenvironment for efficient cancer therapy. Indeed, without affecting the global number of (CD45
CONCLUSION
Collectively, we present evidence that extracellular HMGB1 blockade may complement first-generation cancer immunotherapies by remobilizing antitumor immune response.
Identifiants
pubmed: 33712445
pii: jitc-2020-001966
doi: 10.1136/jitc-2020-001966
pmc: PMC7959241
pii:
doi:
Substances chimiques
HMGB1 Protein
0
HMGB1 protein, human
0
HMGB1 protein, mouse
0
Immune Checkpoint Inhibitors
0
Peptide Fragments
0
S100 Proteins
0
glutamyl-leucyl-lysyl-valyl-leucyl-methionyl-glutamyl-lysyl-glutamyl-leucine
0
Glycyrrhizic Acid
6FO62043WK
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)) 2021. 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: None declared.
Références
Oncoimmunology. 2012 Nov 1;1(8):1223-1225
pubmed: 23243584
N Engl J Med. 2018 Nov 29;379(22):2108-2121
pubmed: 30345906
Cell Death Differ. 2014 Jan;21(1):69-78
pubmed: 23811849
J Exp Med. 2000 Aug 21;192(4):565-70
pubmed: 10952726
Science. 1999 Jul 9;285(5425):248-51
pubmed: 10398600
Free Radic Res. 2010 May;44(5):479-96
pubmed: 20370557
Cancer Immunol Res. 2017 Sep;5(9):755-766
pubmed: 28848055
J Exp Med. 2012 Aug 27;209(9):1519-28
pubmed: 22869893
Mol Med. 2012 Mar 30;18:250-9
pubmed: 22105604
N Engl J Med. 2018 May 31;378(22):2078-2092
pubmed: 29658856
DNA Cell Biol. 2016 Oct;35(10):622-627
pubmed: 27383136
Cancer Res. 1991 Feb 1;51(3):794-8
pubmed: 1846317
Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11942-7
pubmed: 20547845
Oncogenesis. 2019 Feb 22;8(3):17
pubmed: 30796203
Br J Cancer. 2018 May;118(10):1302-1312
pubmed: 29700411
Immunity. 2008 Jul 18;29(1):21-32
pubmed: 18631454
Nat Commun. 2016 May 10;7:11479
pubmed: 27161491
Mol Neurobiol. 2012 Jun;45(3):499-506
pubmed: 22580958
J Clin Oncol. 2016 Jul 20;34(21):2460-7
pubmed: 27138582
Clin Cancer Res. 2018 May 15;24(10):2408-2416
pubmed: 29463549
J Biol Chem. 2004 Feb 27;279(9):7370-7
pubmed: 14660645
Cancer Res. 2012 Jan 1;72(1):230-8
pubmed: 22102692
Biomolecules. 2019 Nov 13;9(11):
pubmed: 31766246
Theranostics. 2019 Jul 9;9(18):5166-5182
pubmed: 31410208
Arthritis Rheum. 2003 Jun;48(6):1693-700
pubmed: 12794838
Ann Rheum Dis. 2013 Aug;72(8):1390-9
pubmed: 23148306
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):296-301
pubmed: 14695889
Transl Oncol. 2018 Apr;11(2):311-329
pubmed: 29413765
Cancer. 1997 Apr 15;79(8):1494-500
pubmed: 9118029
Hepatology. 2012 Jun;55(6):1863-75
pubmed: 22234969
Cancer Res. 2014 Oct 15;74(20):5723-33
pubmed: 25164013
Cell Death Dis. 2018 May 29;9(6):648
pubmed: 29844348
Mod Pathol. 2021 Jan;34(1):116-130
pubmed: 32728225
Tumour Biol. 2016 Mar;37(3):3321-9
pubmed: 26440051
Hepatol Res. 2007 Sep;37 Suppl 2:S287-93
pubmed: 17877497
Oncoimmunology. 2015 Aug 12;5(2):e1075114
pubmed: 27057446
Cancer Immunol Immunother. 2009 Apr;58(4):603-14
pubmed: 18802697
Oncoimmunology. 2015 Mar 19;4(6):e1008334
pubmed: 26155412
Sci Rep. 2017 Dec 4;7(1):16878
pubmed: 29203879
Breast Cancer Res Treat. 2018 Feb;167(3):671-686
pubmed: 29063313
Eur J Biochem. 1973 Sep 21;38(1):14-9
pubmed: 4774120
Oncogene. 2010 Jan 28;29(4):482-91
pubmed: 19881547
J Pathol. 2013 Feb;229(3):460-8
pubmed: 23007879
Exp Hematol. 2012 Apr;40(4):268-78
pubmed: 22245566
Int J Cancer. 2015 Jul 15;137(2):345-58
pubmed: 25492101
J Leukoc Biol. 2014 Apr;95(4):563-74
pubmed: 24453275
JAMA Netw Open. 2019 May 3;2(5):e192535
pubmed: 31050774
Proc Natl Acad Sci U S A. 2014 Feb 25;111(8):3068-73
pubmed: 24469805
Oncogene. 2018 Aug;37(32):4398-4412
pubmed: 29720728
Int Immunopharmacol. 2016 Dec;41:98-105
pubmed: 27865166
Clin Cancer Res. 2012 Aug 15;18(16):4356-64
pubmed: 22718861
EMBO Rep. 2002 Oct;3(10):995-1001
pubmed: 12231511
Oncotarget. 2018 Jan 31;9(12):10665-10680
pubmed: 29535834
Nat Commun. 2020 Jun 2;11(1):2762
pubmed: 32488020
Clin Cancer Res. 2013 Aug 1;19(15):4046-57
pubmed: 23723299
Arthritis Rheum. 2005 Nov;52(11):3639-45
pubmed: 16255056
J Leukoc Biol. 2009 Sep;86(3):633-43
pubmed: 19454652
Chem Biol. 2007 Apr;14(4):431-41
pubmed: 17462578
J Exp Clin Cancer Res. 2019 Jun 13;38(1):255
pubmed: 31196207
Nature. 2012 Apr 18;486(7403):346-52
pubmed: 22522925
J Leukoc Biol. 2007 Jan;81(1):59-66
pubmed: 16966386