Positive Allosteric Modulation of CD11b as a Novel Therapeutic Strategy Against Lung Cancer.
CD11b
activation
immunotherapy
lung cancer
macrophages
Journal
Frontiers in oncology
ISSN: 2234-943X
Titre abrégé: Front Oncol
Pays: Switzerland
ID NLM: 101568867
Informations de publication
Date de publication:
2020
2020
Historique:
received:
18
12
2019
accepted:
20
04
2020
entrez:
13
6
2020
pubmed:
13
6
2020
medline:
13
6
2020
Statut:
epublish
Résumé
Lung cancer is one of the leading causes of cancer-related deaths in the United States. A major hurdle for improved therapies is immune suppression mediated by the tumor and its microenvironment. The lung tumor microenvironment (TME) contains large numbers of tumor-associated macrophages (TAMs), which suppress the adaptive immune response, increase neo-vascularization of the tumor, and provide pro-tumor factors to promote tumor growth. CD11b is highly expressed on myeloid cells, including TAMs, where it forms a heterodimeric integrin receptor with CD18 (known as CD11b/CD18, Mac-1, CR3, and αMβ2), and plays an important role in recruitment and biological functions of these cells, and is a validated therapeutic target. Here, we describe our pre-clinical studies targeting CD11b in the context of lung cancer, using pharmacologic and genetic approaches that work via positive allosteric modulation of CD11b function. GB1275 is a novel small molecule modulator of CD11b that is currently in Phase 1/2 clinical development. We assess GB1275 treatment effects on tumor growth and immune infiltrates in the murine Lewis Lung Carcinoma (LLC) syngeneic tumor model. Additionally, as an orthogonal approach to determine mechanisms of action, we utilize our recently developed novel CD11b knock-in (KI) mouse that constitutively expresses CD11b containing an activating isoleucine to glycine substitution at residue 332 in the ligand binding CD11b A-domain (I332G) that acts as a positive allosteric modulator of CD11b activity. We report that pharmacologic modulation of CD11b with GB1275 significantly reduces LLC tumor growth. CD11b KI mice similarly show significant reduction in both the size and rate of LLC tumor growth, as compared to WT mice, mimicking our observed treatment effects with GB1275. Tumor profiling revealed a significant reduction in TAM infiltration in GB1275-treated and in CD11b KI mice, increase in the ratio of M1/M2-like TAMs, and concomitant increase in cytotoxic T cells. The profiling also showed a significant decrease in CCL2 levels and a concomitant reduction in Ly6C
Identifiants
pubmed: 32528880
doi: 10.3389/fonc.2020.00748
pmc: PMC7253726
doi:
Types de publication
Journal Article
Langues
eng
Pagination
748Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK084195
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA203890
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA244938
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA248917
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107984
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA177670
Pays : United States
Informations de copyright
Copyright © 2020 Geraghty, Rajagopalan, Aslam, Pohlman, Venkatesh, Zloza, Cimbaluk, DeNardo and Gupta.
Références
Front Immunol. 2015 Jun 26;6:332
pubmed: 26167165
J Thorac Oncol. 2010 Oct;5(10):1507-15
pubmed: 20802348
Front Immunol. 2019 Feb 01;9:3101
pubmed: 30774636
Eur Respir J. 2009 Jan;33(1):118-26
pubmed: 19118225
N Engl J Med. 2015 May 21;372(21):2018-28
pubmed: 25891174
Nature. 2014 Nov 6;515(7525):130-3
pubmed: 25337873
Clin Cancer Res. 2000 Aug;6(8):3282-9
pubmed: 10955814
Nat Commun. 2018 Dec 19;9(1):5379
pubmed: 30568188
Cell Metab. 2012 Apr 4;15(4):432-7
pubmed: 22482726
Sci Signal. 2011 Sep 6;4(189):ra57
pubmed: 21900205
J Biol Chem. 2000 Dec 8;275(49):38762-7
pubmed: 11034990
Cancer Cell. 2011 Jun 14;19(6):715-27
pubmed: 21665146
Cancer Res. 2006 Feb 15;66(4):2146-52
pubmed: 16489015
Cell. 2012 Sep 14;150(6):1121-34
pubmed: 22980976
Thorac Cancer. 2018 Jul;9(7):775-784
pubmed: 29722145
Front Immunol. 2019 Jul 25;10:1611
pubmed: 31402908
Cell. 2010 Apr 2;141(1):39-51
pubmed: 20371344
F1000Res. 2016 Oct 4;5:
pubmed: 27781085
Cancer Cell. 2015 Apr 13;27(4):462-72
pubmed: 25858805
Nat Rev Clin Oncol. 2017 Jul;14(7):399-416
pubmed: 28117416
J Immunol. 2017 Oct 1;199(7):2191-2193
pubmed: 28923980
Front Immunol. 2018 Aug 31;9:1977
pubmed: 30233579
Nat Med. 2015 Aug;21(8):938-945
pubmed: 26193342
PLoS One. 2013 Dec 18;8(12):e82241
pubmed: 24367507
Cancer Res. 2007 Mar 15;67(6):2649-56
pubmed: 17363585
JCI Insight. 2016 Sep 8;1(14):e89014
pubmed: 27699239
Oncotarget. 2019 Dec 24;10(67):7142-7155
pubmed: 31903172
J Biol Chem. 2009 Dec 4;284(49):34342-54
pubmed: 19833726
Cancer Discov. 2011 Jun;1(1):54-67
pubmed: 22039576
Nat Commun. 2017 Jul 24;8:16041
pubmed: 28737175
Neoplasia. 2013 Jan;15(1):85-94
pubmed: 23359264
Sci Transl Med. 2019 Jul 3;11(499):
pubmed: 31270275
Cancer Cell. 2016 Aug 8;30(2):365
pubmed: 27505682
Cancer Cell. 2014 Nov 10;26(5):638-52
pubmed: 25446897
J Clin Invest. 2017 Apr 3;127(4):1271-1283
pubmed: 28263189
Immunology. 2018 Nov;155(3):285-293
pubmed: 29963704
Front Immunol. 2018 Jan 17;8:2004
pubmed: 29387063
BMC Cancer. 2010 Mar 25;10:112
pubmed: 20338029
Immunity. 2014 Feb 20;40(2):274-88
pubmed: 24530056
Nature. 2011 Jun 08;475(7355):222-5
pubmed: 21654748
Cancer Cell. 2019 Apr 15;35(4):588-602.e10
pubmed: 30930117
Curr Protoc Immunol. 2001 May;Chapter 4:Unit 4.1
pubmed: 18432792
J Clin Invest. 2012 Mar;122(3):787-95
pubmed: 22378047
Trends Immunol. 2019 Apr;40(4):310-327
pubmed: 30890304
Cancer Res. 2010 Jan 1;70(1):109-18
pubmed: 20028856
Nature. 2012 Sep 27;489(7417):519-25
pubmed: 22960745
Expert Rev Anticancer Ther. 2017 Mar;17(3):199-201
pubmed: 28129007
Nat Rev Cancer. 2004 Jan;4(1):71-8
pubmed: 14708027
Immunity. 2014 Nov 20;41(5):815-29
pubmed: 25453823
J Clin Invest. 2006 Mar;116(3):652-62
pubmed: 16498499
Nat Biotechnol. 2000 Aug;18(8):817-8
pubmed: 10932141
Muscle Nerve. 2015 Aug;52(2):307-8
pubmed: 25759003
Nat Rev Immunol. 2019 Jun;19(6):369-382
pubmed: 30718830