Deep immune profiling reveals targetable mechanisms of immune evasion in immune checkpoint inhibitor-refractory glioblastoma.
Animals
Brain Neoplasms
/ immunology
CTLA-4 Antigen
/ antagonists & inhibitors
Cell Line, Tumor
Glioblastoma
/ immunology
Humans
Immune Checkpoint Inhibitors
/ administration & dosage
Membrane Proteins
/ administration & dosage
Mice
Programmed Cell Death 1 Receptor
/ antagonists & inhibitors
T-Lymphocytes, Regulatory
/ metabolism
Tumor Escape
/ drug effects
Xenograft Model Antitumor Assays
biomarkers
brain neoplasms
dendritic cells
immunotherapy
tumor
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:
06 2021
06 2021
Historique:
accepted:
10
03
2021
entrez:
4
6
2021
pubmed:
5
6
2021
medline:
21
12
2021
Statut:
ppublish
Résumé
Glioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed. We used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations. ICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation. Our data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.
Sections du résumé
BACKGROUND
Glioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.
METHODS
We used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.
RESULTS
ICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.
CONCLUSIONS
Our data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.
Identifiants
pubmed: 34083417
pii: jitc-2020-002181
doi: 10.1136/jitc-2020-002181
pmc: PMC8183210
pii:
doi:
Substances chimiques
CTLA-4 Antigen
0
CTLA4 protein, human
0
Immune Checkpoint Inhibitors
0
Membrane Proteins
0
PDCD1 protein, human
0
Programmed Cell Death 1 Receptor
0
flt3 ligand protein
0
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : K08 CA201591
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA176287
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063720
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA082103
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA194511
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA097257
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA223484
Pays : United States
Organisme : NIH HHS
ID : S10 OD018040
Pays : United States
Organisme : NCI NIH HHS
ID : R33 CA183692
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA222965
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007618
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105068
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA217864
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA221969
Pays : United States
Organisme : Cancer Research UK
ID : A28592
Pays : United Kingdom
Informations de copyright
© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: There are no competing interests.
Références
J Virol. 2015 Aug;89(15):7922-31
pubmed: 25995253
Cancer Res. 1970 Sep;30(9):2394-400
pubmed: 5475483
Nat Biotechnol. 2013 Jun;31(6):545-52
pubmed: 23685480
Nat Commun. 2018 Nov 2;9(1):4593
pubmed: 30389931
Nature. 2020 Jan;577(7792):689-694
pubmed: 31942068
Cancer Res. 2012 Dec 1;72(23):6130-41
pubmed: 23026134
Cell. 2020 Jun 25;181(7):1643-1660.e17
pubmed: 32470396
Immunity. 2014 Jul 17;41(1):14-20
pubmed: 25035950
Oncoimmunology. 2018 Sep 5;7(12):e1501137
pubmed: 30524896
Lancet Oncol. 2016 Jul;17(7):976-983
pubmed: 27267608
Front Immunol. 2020 May 07;11:835
pubmed: 32457755
Immunity. 2014 Jul 17;41(1):127-40
pubmed: 25035957
Clin Cancer Res. 2017 Jan 1;23(1):124-136
pubmed: 27358487
J Clin Invest. 2017 Aug 1;127(8):2930-2940
pubmed: 28650338
Nat Rev Immunol. 2019 Feb;19(2):89-103
pubmed: 30464294
Cancer Cell. 2020 Mar 16;37(3):289-307.e9
pubmed: 32183949
J Clin Oncol. 2000 Dec 1;18(23):3883-93
pubmed: 11099317
Proc Natl Acad Sci U S A. 2018 Feb 13;115(7):E1540-E1549
pubmed: 29386395
J Interferon Cytokine Res. 2001 Aug;21(8):621-9
pubmed: 11559440
Cancer Immunol Immunother. 2014 Aug;63(8):847-57
pubmed: 24878890
Oncotarget. 2017 Oct 6;8(53):91779-91794
pubmed: 29207684
Clin Cancer Res. 2003 Nov 1;9(14):5228-37
pubmed: 14614003
Cancer Immunol Res. 2016 Feb;4(2):124-35
pubmed: 26546453
Cancer Cell. 2017 Mar 13;31(3):326-341
pubmed: 28292436
JCI Insight. 2019 Nov 14;4(22):
pubmed: 31600167
Nat Commun. 2020 Feb 18;11(1):931
pubmed: 32071302
Bioinformatics. 2010 Jan 1;26(1):139-40
pubmed: 19910308
Cell. 2015 Jul 2;162(1):184-97
pubmed: 26095251
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Science. 2011 May 6;332(6030):687-96
pubmed: 21551058
Cytometry A. 2015 Jul;87(7):636-45
pubmed: 25573116
Nature. 2020 Apr;580(7804):517-523
pubmed: 32322066
Nat Med. 2020 Jan;26(1):39-46
pubmed: 31873309
JCI Insight. 2018 Nov 2;3(21):
pubmed: 30385717
Neuro Oncol. 2020 May 15;22(5):639-651
pubmed: 31793634
Immunity. 2013 Jul 25;39(1):1-10
pubmed: 23890059
JAMA. 2017 Dec 19;318(23):2306-2316
pubmed: 29260225
Immunity. 2016 Apr 19;44(4):924-38
pubmed: 27096321
Nat Commun. 2020 Aug 6;11(1):3912
pubmed: 32764562
Science. 2018 Mar 23;359(6382):1350-1355
pubmed: 29567705
Cell. 2020 Jun 25;181(7):1626-1642.e20
pubmed: 32470397
Cancer Res. 2012 Oct 15;72(20):5240-9
pubmed: 22850422
Nat Rev Immunol. 2012 Apr 10;12(5):339-51
pubmed: 22487654
Nature. 2015 Jul 9;523(7559):231-5
pubmed: 25970248
Neuro Oncol. 2017 Jun 1;19(6):796-807
pubmed: 28115578
J Exp Med. 2015 Jun 29;212(7):991-9
pubmed: 26077718
Immunity. 2019 Feb 19;50(2):477-492.e8
pubmed: 30737146