Profiling specific cell populations within the inflammatory tumor microenvironment by oscillating-gradient diffusion-weighted MRI.
T-lymphocytes
immunotherapy
macrophages
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 2023
03 2023
Historique:
accepted:
27
02
2023
entrez:
14
3
2023
pubmed:
15
3
2023
medline:
17
3
2023
Statut:
ppublish
Résumé
The inflammatory tumor microenvironment (TME) is formed by various immune cells, being closely associated with tumorigenesis. Especially, the interaction between tumor-infiltrating T-cells and macrophages has a crucial impact on tumor progression and metastatic spread. The purpose of this study was to investigate whether oscillating-gradient diffusion-weighted MRI (OGSE-DWI) enables a cell size-based discrimination between different cell populations of the TME. Sine-shaped OGSE-DWI was combined with the Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion (IMPULSED) approach to measure microscale diffusion distances, here relating to cell sizes. The accuracy of IMPULSED-derived cell radii was evaluated using in vitro spheroid models, consisting of either pure cancer cells, macrophages, or T-cells. Subsequently, in vivo experiments aimed to assess changes within the TME and its specific immune cell composition in syngeneic murine breast cancer models with divergent degrees of malignancy (4T1, 67NR) during tumor progression, clodronate liposome-mediated depletion of macrophages, and immune checkpoint inhibitor (ICI) treatment. Ex vivo analysis of IMPULSED-derived cell radii was conducted by immunohistochemical wheat germ agglutinin staining of cell membranes, while intratumoral immune cell composition was analyzed by CD3 and F4/80 co-staining. OGSE-DWI detected mean cell radii of 8.8±1.3 µm for 4T1, 8.2±1.4 µm for 67NR, 13.0±1.7 for macrophage, and 3.8±1.8 µm for T-cell spheroids. While T-cell infiltration during progression of 4T1 tumors was observed by decreasing mean cell radii from 9.7±1.0 to 5.0±1.5 µm, increasing amount of intratumoral macrophages during progression of 67NR tumors resulted in increasing mean cell radii from 8.9±1.2 to 12.5±1.1 µm. After macrophage depletion, mean cell radii decreased from 6.3±1.7 to 4.4±0.5 µm. T-cell infiltration after ICI treatment was captured by decreasing mean cell radii in both tumor models, with more pronounced effects in the 67NR tumor model. OGSE-DWI provides a versatile tool for non-invasive profiling of the inflammatory TME by assessing the dominating cell type T-cells or macrophages.
Sections du résumé
BACKGROUND
The inflammatory tumor microenvironment (TME) is formed by various immune cells, being closely associated with tumorigenesis. Especially, the interaction between tumor-infiltrating T-cells and macrophages has a crucial impact on tumor progression and metastatic spread. The purpose of this study was to investigate whether oscillating-gradient diffusion-weighted MRI (OGSE-DWI) enables a cell size-based discrimination between different cell populations of the TME.
METHODS
Sine-shaped OGSE-DWI was combined with the Imaging Microstructural Parameters Using Limited Spectrally Edited Diffusion (IMPULSED) approach to measure microscale diffusion distances, here relating to cell sizes. The accuracy of IMPULSED-derived cell radii was evaluated using in vitro spheroid models, consisting of either pure cancer cells, macrophages, or T-cells. Subsequently, in vivo experiments aimed to assess changes within the TME and its specific immune cell composition in syngeneic murine breast cancer models with divergent degrees of malignancy (4T1, 67NR) during tumor progression, clodronate liposome-mediated depletion of macrophages, and immune checkpoint inhibitor (ICI) treatment. Ex vivo analysis of IMPULSED-derived cell radii was conducted by immunohistochemical wheat germ agglutinin staining of cell membranes, while intratumoral immune cell composition was analyzed by CD3 and F4/80 co-staining.
RESULTS
OGSE-DWI detected mean cell radii of 8.8±1.3 µm for 4T1, 8.2±1.4 µm for 67NR, 13.0±1.7 for macrophage, and 3.8±1.8 µm for T-cell spheroids. While T-cell infiltration during progression of 4T1 tumors was observed by decreasing mean cell radii from 9.7±1.0 to 5.0±1.5 µm, increasing amount of intratumoral macrophages during progression of 67NR tumors resulted in increasing mean cell radii from 8.9±1.2 to 12.5±1.1 µm. After macrophage depletion, mean cell radii decreased from 6.3±1.7 to 4.4±0.5 µm. T-cell infiltration after ICI treatment was captured by decreasing mean cell radii in both tumor models, with more pronounced effects in the 67NR tumor model.
CONCLUSIONS
OGSE-DWI provides a versatile tool for non-invasive profiling of the inflammatory TME by assessing the dominating cell type T-cells or macrophages.
Identifiants
pubmed: 36918222
pii: jitc-2022-006092
doi: 10.1136/jitc-2022-006092
pmc: PMC10016257
pii:
doi:
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)) 2023. 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
Front Immunol. 2019 May 22;10:1078
pubmed: 31231358
Int J Stem Cells. 2020 Jul 30;13(2):287-294
pubmed: 32323512
Nat Rev Neurosci. 2003 Jun;4(6):469-80
pubmed: 12778119
Sci Rep. 2020 Feb 3;10(1):1711
pubmed: 32015362
Q J Nucl Med Mol Imaging. 2018 Mar;62(1):56-77
pubmed: 29191000
J Magn Reson. 2013 Dec;237:49-62
pubmed: 24140623
Cancer Microenviron. 2012 Apr;5(1):5-18
pubmed: 21922183
J Immunother Cancer. 2020 Jun;8(1):
pubmed: 32581044
NMR Biomed. 2022 Dec;35(12):e4799
pubmed: 35794795
Front Oncol. 2021 Mar 11;11:610303
pubmed: 33777750
Int Arch Allergy Immunol. 1999 May;119(1):6-12
pubmed: 10341315
Oxid Med Cell Longev. 2021 Feb 2;2021:8865791
pubmed: 33628389
Br J Cancer. 2019 Jan;120(1):45-53
pubmed: 30413828
Mol Imaging Biol. 2020 Feb;22(1):66-72
pubmed: 31098983
Magn Reson Med. 2023 Jan;89(1):411-422
pubmed: 36063493
Cancer Immunol Res. 2017 Oct;5(10):871-884
pubmed: 28848054
Radiology. 1986 Nov;161(2):401-7
pubmed: 3763909
Biochem Biophys Rep. 2021 Feb 01;25:100916
pubmed: 33553685
Results Probl Cell Differ. 2017;62:161-179
pubmed: 28455709
Nat Commun. 2020 Jul 30;11(1):3801
pubmed: 32732879
Cancer Res. 2008 Jul 15;68(14):5941-7
pubmed: 18632649
J Liposome Res. 2002 Feb-May;12(1-2):81-94
pubmed: 12604042
Biol Pharm Bull. 2018 Apr 1;41(4):487-503
pubmed: 29332929
Front Immunol. 2021 Oct 20;12:751594
pubmed: 34745124
J Magn Reson. 2009 Oct;200(2):189-97
pubmed: 19616979
NMR Biomed. 2017 Mar;30(3):
pubmed: 28230327
Magn Reson Med. 2020 Jun;83(6):2002-2014
pubmed: 31765494
Magn Reson Med. 2017 Jul;78(1):156-164
pubmed: 27495144
Magn Reson Med. 2023 Mar;89(3):1193-1206
pubmed: 36372982
Breast Cancer Res. 2014 Nov 29;16(6):488
pubmed: 25432519
Magn Reson Med. 2003 Feb;49(2):206-15
pubmed: 12541239
Am J Physiol Lung Cell Mol Physiol. 2014 Feb 15;306(4):L341-50
pubmed: 24375800
Cell Death Differ. 2010 Jun;17(6):922-30
pubmed: 20010783
J Vis Exp. 2019 Aug 8;(150):
pubmed: 31449247
Nat Rev Clin Oncol. 2019 Jul;16(7):442-458
pubmed: 30718844
Front Oncol. 2022 Nov 02;12:1000036
pubmed: 36408159
Brief Bioinform. 2021 Mar 22;22(2):2020-2031
pubmed: 32141494
Infect Immun. 2000 Jan;68(1):165-9
pubmed: 10603383
NMR Biomed. 2019 Apr;32(4):e3998
pubmed: 30321478
Mol Cancer. 2020 Aug 6;19(1):120
pubmed: 32762681
Theranostics. 2017 Mar 1;7(5):1164-1176
pubmed: 28435456
Asian Pac J Cancer Prev. ;18(10):2689-2693
pubmed: 29072393
Adv Drug Deliv Rev. 2014 Feb;66:90-100
pubmed: 24064465
J Magn Reson. 2017 Feb;275:98-113
pubmed: 28040623
BMC Syst Biol. 2013;7 Suppl 1:S4
pubmed: 24268033
Front Immunol. 2018 Jul 26;9:1571
pubmed: 30093900