Dose-Specific Intratumoral GM-CSF Modulates Breast Tumor Oxygenation and Antitumor Immunity.
Journal
Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
Titre abrégé: J Immunol
Pays: United States
ID NLM: 2985117R
Informations de publication
Date de publication:
15 11 2023
15 11 2023
Historique:
received:
11
05
2023
accepted:
11
09
2023
pmc-release:
15
11
2024
medline:
8
11
2023
pubmed:
27
9
2023
entrez:
27
9
2023
Statut:
ppublish
Résumé
GM-CSF has been employed as an adjuvant to cancer immunotherapy with mixed results based on dosage. We previously showed that GM-CSF regulated tumor angiogenesis by stimulating soluble vascular endothelial growth factor (VEGF) receptor-1 from monocytes/macrophages in a dose-dependent manner that neutralized free VEGF, and intratumoral injections of high-dose GM-CSF ablated blood vessels and worsened hypoxia in orthotopic polyoma middle T Ag (PyMT) triple-negative breast cancer (TNBC). In this study, we assessed both immunoregulatory and oxygen-regulatory components of low-dose versus high-dose GM-CSF to compare effects on tumor oxygen, vasculature, and antitumor immunity. We performed intratumoral injections of low-dose GM-CSF or saline controls for 3 wk in FVB/N PyMT TNBC. Low-dose GM-CSF uniquely reduced tumor hypoxia and normalized tumor vasculature by increasing NG2+ pericyte coverage on CD31+ endothelial cells. Priming of "cold," anti-PD1-resistant PyMT tumors with low-dose GM-CSF (hypoxia reduced) sensitized tumors to anti-PD1, whereas high-dose GM-CSF (hypoxia exacerbated) did not. Low-dose GM-CSF reduced hypoxic and inflammatory tumor-associated macrophage (TAM) transcriptional profiles; however, no phenotypic modulation of TAMs or tumor-infiltrating lymphocytes were observed by flow cytometry. In contrast, high-dose GM-CSF priming increased infiltration of TAMs lacking the MHC class IIhi phenotype or immunostimulatory marker expression, indicating an immunosuppressive phenotype under hypoxia. However, in anti-PD1 (programmed cell death 1)-susceptible BALB/c 4T1 tumors (considered hot versus PyMT), high-dose GM-CSF increased MHC class IIhi TAMs and immunostimulatory molecules, suggesting disparate effects of high-dose GM-CSF across PyMT versus 4T1 TNBC models. Our data demonstrate a (to our knowledge) novel role for low-dose GM-CSF in reducing tumor hypoxia for synergy with anti-PD1 and highlight why dosage and setting of GM-CSF in cancer immunotherapy regimens require careful consideration.
Identifiants
pubmed: 37756529
pii: 265942
doi: 10.4049/jimmunol.2300326
pmc: PMC10656117
mid: NIHMS1931840
doi:
Substances chimiques
Granulocyte-Macrophage Colony-Stimulating Factor
83869-56-1
Vascular Endothelial Growth Factor A
0
Oxygen
S88TT14065
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1589-1604Subventions
Organisme : NIBIB NIH HHS
ID : R00 EB023990
Pays : United States
Organisme : NCRR NIH HHS
ID : P20 RR016440
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB032321
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM133369
Pays : United States
Organisme : NCRR NIH HHS
ID : P30 RR032138
Pays : United States
Organisme : NIGMS NIH HHS
ID : U54 GM104942
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM121322
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016058
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA192064
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM103488
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS125056
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB023888
Pays : United States
Organisme : NIH HHS
ID : S10 OD016165
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI167972
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA194013
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM103434
Pays : United States
Organisme : NIBIB NIH HHS
ID : R21 EB030228
Pays : United States
Informations de copyright
Copyright © 2023 by The American Association of Immunologists, Inc.
Références
AAPS PharmSciTech. 2021 Jun 24;22(5):191
pubmed: 34169366
Biochim Biophys Acta. 2016 Mar;1863(3):382-391
pubmed: 26079100
Sci Rep. 2021 Aug 4;11(1):15840
pubmed: 34349149
J Magn Reson. 2006 Jan;178(1):42-55
pubmed: 16188474
J Magn Reson. 2019 Aug;305:94-103
pubmed: 31238278
J Exp Clin Cancer Res. 2021 Jan 9;40(1):24
pubmed: 33422072
Exp Mol Med. 2016 Jul 01;48(7):e242
pubmed: 27364892
Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):18632-7
pubmed: 24167277
Bioinformatics. 2014 Apr 1;30(7):923-30
pubmed: 24227677
Exp Mol Med. 2018 Dec 13;50(12):1-11
pubmed: 30546008
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17561-6
pubmed: 23045683
Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3539-43
pubmed: 8097319
Immunity. 2004 Dec;21(6):831-42
pubmed: 15589171
Nature. 2017 May 25;545(7655):495-499
pubmed: 28514441
Front Immunol. 2019 Nov 15;10:2679
pubmed: 31803190
J Immunother Cancer. 2021 Feb;9(2):
pubmed: 33602696
Breast Cancer Res Treat. 2022 Jul;194(1):65-78
pubmed: 35482127
J Transl Med. 2015 Jul 05;13:214
pubmed: 26143264
Proc Natl Acad Sci U S A. 1998 Oct 27;95(22):13141-6
pubmed: 9789055
J Clin Oncol. 2015 Dec 1;33(34):4066-76
pubmed: 26351350
Front Oncol. 2020 Sep 10;10:1771
pubmed: 33014872
Front Oncol. 2018 Mar 12;8:49
pubmed: 29594035
Nat Biotechnol. 2007 Aug;25(8):911-20
pubmed: 17664940
Antioxid Redox Signal. 2018 May 20;28(15):1365-1377
pubmed: 29132215
Eur J Surg Oncol. 2007 Dec;33(10):1169-76
pubmed: 17512160
Melanoma Manag. 2020 Jul 29;7(3):MMT49
pubmed: 32922731
Bioinformatics. 2011 Jun 15;27(12):1739-40
pubmed: 21546393
Nature. 1989 Feb 2;337(6206):471-3
pubmed: 2464767
Theranostics. 2018 Nov 12;8(21):5842-5854
pubmed: 30613266
Cancer Immunol Res. 2014 Oct;2(10):949-61
pubmed: 25116755
Cancer Cell. 2012 Jun 12;21(6):822-35
pubmed: 22698406
Bio Protoc. 2019 Dec 20;9(24):
pubmed: 31867411
Cancer Cell. 2014 Nov 10;26(5):605-22
pubmed: 25517747
J Immunother. 2013 Nov-Dec;36(9):477-89
pubmed: 24145359
J Immunother Cancer. 2021 Aug;9(8):
pubmed: 34389617
J Leukoc Biol. 2009 Nov;86(5):1065-73
pubmed: 19741157
RSC Adv. 2019;9(60):35073-35076
pubmed: 32483485
Sci Rep. 2017 Nov 7;7(1):14655
pubmed: 29116108
Cancers (Basel). 2022 Feb 13;14(4):
pubmed: 35205675
Appl Magn Reson. 2020 Oct;51(9-10):1117-1124
pubmed: 33642700
Oncoimmunology. 2015 Jul 27;4(9):e985930
pubmed: 26405612
Front Immunol. 2022 Jul 05;13:901277
pubmed: 35865534
J Vis Exp. 2018 Mar 16;(133):
pubmed: 29608148
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Clin Exp Metastasis. 2005;22(1):47-59
pubmed: 16132578
Nucleic Acids Res. 2019 May 7;47(8):e47
pubmed: 30783653
Am J Pathol. 2003 Nov;163(5):2113-26
pubmed: 14578209
Semin Radiat Oncol. 1996 Jan;6(1):37-45
pubmed: 10717160
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Cancer Res. 2009 Mar 1;69(5):2133-40
pubmed: 19223554
Acad Radiol. 2014 Feb;21(2):197-206
pubmed: 24439333
RSC Adv. 2021 Jul 27;11(42):25951-25954
pubmed: 34354828
Cancer Res. 2011 May 1;71(9):3364-76
pubmed: 21415165
Drug Resist Updat. 2021 Dec;59:100787
pubmed: 34840068
J Clin Invest. 2006 Oct;116(10):2610-21
pubmed: 17016557
J Clin Invest. 2021 Apr 15;131(8):
pubmed: 33855973
J Magn Reson. 2017 Aug;281:44-50
pubmed: 28549338
Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):856-61
pubmed: 20080765
Cancer Res. 2004 Sep 1;64(17):6337-43
pubmed: 15342423
J Magn Reson. 2022 Dec;345:107308
pubmed: 36356489
BMC Cancer. 2012 Jul 23;12:306
pubmed: 22824040
J Immunol. 1999 May 15;162(10):5728-37
pubmed: 10229805
Blood. 2004 Oct 15;104(8):2224-34
pubmed: 15231578
J Cancer. 2020 May 18;11(15):4474-4494
pubmed: 32489466
Transl Oncol. 2022 Jun;20:101405
pubmed: 35339889
Cancer Res. 2016 Jan 1;76(1):35-42
pubmed: 26573801