A comprehensive profiling of the immune microenvironment of breast cancer brain metastases.
brain metastases
breast cancer
immune biomarkers
immune microenvironment
multiplex immunofluorescence
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
01 12 2022
01 12 2022
Historique:
pubmed:
25
5
2022
medline:
3
12
2022
entrez:
24
5
2022
Statut:
ppublish
Résumé
Despite potential clinical implications, the complexity of breast cancer (BC) brain metastases (BM) immune microenvironment is poorly understood. Through multiplex immunofluorescence, we here describe the main features of BCBM immune microenvironment (density and spatial distribution) and evaluate its prognostic impact. Sixty BCBM from patients undergoing neurosurgery at three institutions (2003-2018) were comprehensively assessed using two multiplex immunofluorescence panels (CD4, CD8, Granzyme B, FoxP3, CD68, pan-cytokeratin, DAPI; CD3, PD-1, PD-L1, LAG-3, TIM-3, CD163, pan-cytokeratin, DAPI). The prognostic impact of immune subpopulations and cell-to-cell spatial interactions was evaluated. Subtype-related differences in BCBM immune microenvironment and its prognostic impact were observed. While in HR-/HER2- BM and HER2+ BM, higher densities of intra-tumoral CD8+ lymphocytes were associated with significantly longer OS (HR 0.16 and 0.20, respectively), in HR+/HER2- BCBMs a higher CD4+FoxP3+/CD8+ cell ratio in the stroma was associated with worse OS (HR 5.4). Moreover, a higher density of intra-tumoral CD163+ M2-polarized microglia/macrophages in BCBMs was significantly associated with worse OS in HR-/HER2- and HR+/HER2- BCBMs (HR 6.56 and 4.68, respectively), but not in HER2+ BCBMs. In HER2+ BCBMs, multiplex immunofluorescence highlighted a negative prognostic role of PD-1/PD-L1 interaction: patients with a higher percentage of PD-L1+ cells spatially interacting with (within a 20 µm radius) PD-1+ cells presented a significantly worse OS (HR 4.60). Our results highlight subtype-related differences in BCBM immune microenvironment and identify two potential therapeutic targets, M2 microglia/macrophage polarization in HER2- and PD-1/PD-L1 interaction in HER2+ BCBMs, which warrant future exploration in clinical trials.
Sections du résumé
BACKGROUND
Despite potential clinical implications, the complexity of breast cancer (BC) brain metastases (BM) immune microenvironment is poorly understood. Through multiplex immunofluorescence, we here describe the main features of BCBM immune microenvironment (density and spatial distribution) and evaluate its prognostic impact.
METHODS
Sixty BCBM from patients undergoing neurosurgery at three institutions (2003-2018) were comprehensively assessed using two multiplex immunofluorescence panels (CD4, CD8, Granzyme B, FoxP3, CD68, pan-cytokeratin, DAPI; CD3, PD-1, PD-L1, LAG-3, TIM-3, CD163, pan-cytokeratin, DAPI). The prognostic impact of immune subpopulations and cell-to-cell spatial interactions was evaluated.
RESULTS
Subtype-related differences in BCBM immune microenvironment and its prognostic impact were observed. While in HR-/HER2- BM and HER2+ BM, higher densities of intra-tumoral CD8+ lymphocytes were associated with significantly longer OS (HR 0.16 and 0.20, respectively), in HR+/HER2- BCBMs a higher CD4+FoxP3+/CD8+ cell ratio in the stroma was associated with worse OS (HR 5.4). Moreover, a higher density of intra-tumoral CD163+ M2-polarized microglia/macrophages in BCBMs was significantly associated with worse OS in HR-/HER2- and HR+/HER2- BCBMs (HR 6.56 and 4.68, respectively), but not in HER2+ BCBMs. In HER2+ BCBMs, multiplex immunofluorescence highlighted a negative prognostic role of PD-1/PD-L1 interaction: patients with a higher percentage of PD-L1+ cells spatially interacting with (within a 20 µm radius) PD-1+ cells presented a significantly worse OS (HR 4.60).
CONCLUSIONS
Our results highlight subtype-related differences in BCBM immune microenvironment and identify two potential therapeutic targets, M2 microglia/macrophage polarization in HER2- and PD-1/PD-L1 interaction in HER2+ BCBMs, which warrant future exploration in clinical trials.
Identifiants
pubmed: 35609559
pii: 6591493
doi: 10.1093/neuonc/noac136
pmc: PMC9713504
doi:
Substances chimiques
B7-H1 Antigen
0
Biomarkers, Tumor
0
Forkhead Transcription Factors
0
Keratins
68238-35-7
Programmed Cell Death 1 Receptor
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2146-2158Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
Références
Lancet Oncol. 2019 Mar;20(3):371-382
pubmed: 30765258
BMC Cancer. 2021 Apr 6;21(1):357
pubmed: 33823818
NPJ Precis Oncol. 2021 Mar 19;5(1):23
pubmed: 33742063
Nat Commun. 2017 Apr 27;8:15095
pubmed: 28447602
Nat Commun. 2021 Sep 27;12(1):5668
pubmed: 34580291
Front Oncol. 2020 Jan 24;9:1512
pubmed: 32039007
Breast Cancer Res Treat. 2019 Jul;176(2):321-328
pubmed: 31016641
Immunol Rev. 2009 May;229(1):259-70
pubmed: 19426227
Front Immunol. 2013 Dec 10;4:449
pubmed: 24339828
Front Immunol. 2019 Aug 20;10:1941
pubmed: 31481958
Antioxid Redox Signal. 2013 Jun 10;18(17):2352-63
pubmed: 22900885
Front Oncol. 2021 Feb 22;11:579351
pubmed: 33692946
Semin Cancer Biol. 2018 Oct;52(Pt 2):16-25
pubmed: 29024776
Int J Cancer. 2020 Jul 15;147(2):423-439
pubmed: 31721169
Oncoimmunology. 2018 Aug 23;7(11):e1502128
pubmed: 30377566
Sci Rep. 2016 Nov 14;6:36956
pubmed: 27841362
NPJ Breast Cancer. 2021 Feb 12;7(1):12
pubmed: 33579951
Front Oncol. 2016 Dec 07;6:256
pubmed: 28003994
Ann Oncol. 2018 Jan 1;29(1):170-177
pubmed: 29045543
Methods. 2014 Nov;70(1):46-58
pubmed: 25242720
Theranostics. 2020 Feb 10;10(7):2949-2964
pubmed: 32194848
J Immunother Cancer. 2015 Oct 20;3:47
pubmed: 26500776
Br J Cancer. 2019 Dec;121(12):991-1000
pubmed: 31719684
CNS Oncol. 2017 Apr;6(2):139-151
pubmed: 28425754
Oncoimmunology. 2015 May 27;4(10):e1029704
pubmed: 26451298
J Immunother Cancer. 2019 Mar 29;7(1):90
pubmed: 30922362
Nat Rev Clin Oncol. 2017 Dec;14(12):717-734
pubmed: 28741618
Breast Cancer Res. 2016 Apr 27;18(1):43
pubmed: 27117582
Oncotarget. 2015 Dec 1;6(38):40836-49
pubmed: 26517811
J Clin Oncol. 2019 Mar 1;37(7):559-569
pubmed: 30650045
J Immunother Cancer. 2020 Jun;8(1):
pubmed: 32601081
Clin Cancer Res. 2019 Nov 15;25(22):6731-6741
pubmed: 31515462
Breast. 2016 Oct;29:241-50
pubmed: 27481651
Lancet Oncol. 2018 Jan;19(1):40-50
pubmed: 29233559
Oncoimmunology. 2015 Jun 9;5(1):e1057388
pubmed: 26942067
Oncotarget. 2017 Oct 27;8(61):103671-103681
pubmed: 29262592
Eur J Cancer. 2020 Sep;136:7-15
pubmed: 32622323
Glia. 2018 Nov;66(11):2438-2455
pubmed: 30357946
J Clin Oncol. 2004 Sep 1;22(17):3608-17
pubmed: 15337811
Cancer Immunol Immunother. 2019 Dec;68(12):1995-2004
pubmed: 31690954
Cancer Treat Rev. 2016 May;46:9-19
pubmed: 27055087
J Immunother Cancer. 2019 Oct 18;7(1):265
pubmed: 31627744
Mol Cancer Ther. 2021 Mar;20(3):455-466
pubmed: 33402399
Oncoimmunology. 2019 Aug 26;8(11):e1648171
pubmed: 31646095
Nat Commun. 2015 Mar 20;6:6340
pubmed: 25790768
Cancer. 2003 Jun 15;97(12):2972-7
pubmed: 12784331
Front Oncol. 2017 Oct 30;7:251
pubmed: 29164051
Breast Cancer Res. 2018 Jun 22;20(1):62
pubmed: 29929548
Lancet Oncol. 2014 Feb;15(2):e58-68
pubmed: 24480556