Discovery of Biomarkers of Resistance to Immune Checkpoint Blockade in NSCLC Using High-Plex Digital Spatial Profiling.
Digital spatial profiling
IHC
Immunohistochemistry
Immunotherapy resistance
NSCLC
Quantitative immunofluorescence
Journal
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
ISSN: 1556-1380
Titre abrégé: J Thorac Oncol
Pays: United States
ID NLM: 101274235
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
27
01
2022
revised:
17
04
2022
accepted:
20
04
2022
pubmed:
2
5
2022
medline:
10
8
2022
entrez:
1
5
2022
Statut:
ppublish
Résumé
Despite the clinical efficacy of immune checkpoint inhibitors (ICIs) in NSCLC, only approximately 20% of patients remain disease-free at 5 years. Here, we use digital spatial profiling to find candidate biomarker proteins associated with ICI resistance. Pretreatment samples from 56 patients with NSCLC treated with ICI were analyzed using the NanoString GeoMx digital spatial profiling method. A panel of 71 photocleavable oligonucleotide-labeled primary antibodies was used for protein detection in four molecular compartments (tumor, leukocytes, macrophages, and immune stroma). Promising candidates were orthogonally validated with quantitative immunofluorescence. Available pretreatment samples from 39 additional patients with NSCLC who received ICI and 236 non-ICI-treated patients with operable NSCLC were analyzed to provide independent cohort validation. Biomarker discovery using the protein-based molecular compartmentalization strategy allows 284 protein variables to be assessed for association with ICI resistance by univariate analysis using continuous log-scaled data. Of the 71 candidate protein biomarkers, CD66b in the CD45+CD68 molecular compartment (immune stroma) predicted significantly shorter overall survival (OS) (hazard ratio [HR] 1.31, p = 0.016) and was chosen for validation. Orthogonal validation by quantitative immunofluorescence illustrated that CD66b was associated with resistance to ICI therapy but not prognostic for poor outcomes in untreated NSCLC (discovery cohort [OS HR 2.49, p = 0.026], validation cohort [OS HR 2.05, p = 0.046], non-ICI-treated cohort [OS HR 1.67, p = 0.06]). Using the technique, we have discovered that CD66b expression is indicative of resistance to ICI therapy in NSCLC. Given that CD66b identifies neutrophils, further studies are warranted to characterize the role of neutrophils in ICI resistance.
Identifiants
pubmed: 35490853
pii: S1556-0864(22)00212-X
doi: 10.1016/j.jtho.2022.04.009
pmc: PMC9356986
mid: NIHMS1802660
pii:
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
Biomarkers, Tumor
0
Immune Checkpoint Inhibitors
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
991-1001Subventions
Organisme : NCI NIH HHS
ID : P30 CA016359
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA196530
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2022 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Références
Front Immunol. 2021 Jul 14;12:669398
pubmed: 34335570
Front Oncol. 2020 Jun 23;10:654
pubmed: 32656072
JAMA Oncol. 2018 Mar 01;4(3):351-357
pubmed: 29327044
Ther Adv Med Oncol. 2020 Jul 3;12:1758835920937902
pubmed: 32670423
J Thorac Oncol. 2016 Jul;11(7):964-75
pubmed: 27117833
Biomed Rep. 2020 Apr;12(4):204-208
pubmed: 32190309
PLoS Comput Biol. 2021 Feb 17;17(2):e1008257
pubmed: 33596197
Expert Rev Mol Diagn. 2020 May;20(5):509-522
pubmed: 32178550
ISRN Hematol. 2012;2012:915868
pubmed: 22844608
Nat Biotechnol. 2020 May;38(5):586-599
pubmed: 32393914
Immunity. 2020 May 19;52(5):856-871.e8
pubmed: 32289253
Clin Cancer Res. 2020 Aug 15;26(16):4360-4368
pubmed: 32253229
Nat Med. 2020 May;26(5):688-692
pubmed: 32405062
JAMA Oncol. 2019 Aug 01;5(8):1195-1204
pubmed: 31318407
Nat Med. 2002 Nov;8(11):1323-7
pubmed: 12389040
Cancer Cell. 2021 Mar 8;39(3):423-437.e7
pubmed: 33450198
Front Immunol. 2020 Sep 16;11:1749
pubmed: 33042107
JCI Insight. 2019 Jul 25;5:
pubmed: 31343990
J Immunother Cancer. 2021 Apr;9(4):
pubmed: 33833050
Cell Mol Immunol. 2020 Jan;17(1):1-12
pubmed: 31611651
Cancer Discov. 2018 Jul;8(7):822-835
pubmed: 29773717
Blood. 2007 Apr 1;109(7):3084-7
pubmed: 17119118
JAMA Oncol. 2019 Oct 01;5(10):1411-1420
pubmed: 31343665
J Thorac Oncol. 2022 Mar;17(3):399-410
pubmed: 34740862
J Thorac Oncol. 2017 Aug;12(8):1268-1279
pubmed: 28483607
J Thorac Oncol. 2018 Jun;13(6):831-839
pubmed: 29578107
J Thorac Oncol. 2016 Nov;11(11):1927-1939
pubmed: 27496650
J Immunother Cancer. 2020 Mar;8(1):
pubmed: 32238470
BMC Cancer. 2020 Dec 3;20(1):1185
pubmed: 33272262
Nat Rev Cancer. 2020 Sep;20(9):485-503
pubmed: 32694624
Nat Med. 2010 Feb;16(2):219-23
pubmed: 20081861
J Pathol. 2021 Oct;255(2):190-201
pubmed: 34184758
Oncotarget. 2017 Dec 15;9(4):4375-4384
pubmed: 29435109
J Immunother Cancer. 2021 Jul;9(7):
pubmed: 34301813
J Immunother Cancer. 2019 Feb 6;7(1):32
pubmed: 30728077
J Biol Chem. 2002 Mar 22;277(12):10028-36
pubmed: 11792697
JCI Insight. 2019 Dec 19;4(24):
pubmed: 31852845
Sci Rep. 2019 Nov 15;9(1):16891
pubmed: 31729453
Lung Cancer. 2013 Jul;81(1):130-7
pubmed: 23540719
Nat Rev Immunol. 2020 Nov;20(11):651-668
pubmed: 32433532
Clin Cancer Res. 2004 Nov 1;10(21):7252-9
pubmed: 15534099
Blood. 2011 Jun 2;117(22):6050-2; author reply 6053-4
pubmed: 21636720
Front Oncol. 2020 Oct 20;10:568059
pubmed: 33194652
Cancer. 2012 Mar 15;118(6):1726-37
pubmed: 21953630
J Thorac Oncol. 2017 Jun;12(6):943-953
pubmed: 28341226
Nat Genet. 2019 Feb;51(2):202-206
pubmed: 30643254
J Clin Oncol. 2021 Jul 20;39(21):2339-2349
pubmed: 33872070