Targeting MDM2 enhances antileukemia immunity after allogeneic transplantation via MHC-II and TRAIL-R1/2 upregulation.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
08 09 2022
08 09 2022
Historique:
received:
24
02
2022
accepted:
01
07
2022
pubmed:
20
7
2022
medline:
14
9
2022
entrez:
19
7
2022
Statut:
ppublish
Résumé
Patients with acute myeloid leukemia (AML) often achieve remission after allogeneic hematopoietic cell transplantation (allo-HCT) but subsequently die of relapse driven by leukemia cells resistant to elimination by allogeneic T cells based on decreased major histocompatibility complex II (MHC-II) expression and apoptosis resistance. Here we demonstrate that mouse-double-minute-2 (MDM2) inhibition can counteract immune evasion of AML. MDM2 inhibition induced MHC class I and II expression in murine and human AML cells. Using xenografts of human AML and syngeneic mouse models of leukemia, we show that MDM2 inhibition enhanced cytotoxicity against leukemia cells and improved survival. MDM2 inhibition also led to increases in tumor necrosis factor-related apoptosis-inducing ligand receptor-1 and -2 (TRAIL-R1/2) on leukemia cells and higher frequencies of CD8+CD27lowPD-1lowTIM-3low T cells, with features of cytotoxicity (perforin+CD107a+TRAIL+) and longevity (bcl-2+IL-7R+). CD8+ T cells isolated from leukemia-bearing MDM2 inhibitor-treated allo-HCT recipients exhibited higher glycolytic activity and enrichment for nucleotides and their precursors compared with vehicle control subjects. T cells isolated from MDM2 inhibitor-treated AML-bearing mice eradicated leukemia in secondary AML-bearing recipients. Mechanistically, the MDM2 inhibitor-mediated effects were p53-dependent because p53 knockdown abolished TRAIL-R1/2 and MHC-II upregulation, whereas p53 binding to TRAILR1/2 promotors increased upon MDM2 inhibition. The observations in the mouse models were complemented by data from human individuals. Patient-derived AML cells exhibited increased TRAIL-R1/2 and MHC-II expression on MDM2 inhibition. In summary, we identified a targetable vulnerability of AML cells to allogeneic T-cell-mediated cytotoxicity through the restoration of p53-dependent TRAIL-R1/2 and MHC-II production via MDM2 inhibition.
Identifiants
pubmed: 35853161
pii: S0006-4971(22)00920-X
doi: 10.1182/blood.2022016082
pmc: PMC9461473
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
MDM2 protein, human
EC 2.3.2.27
Proto-Oncogene Proteins c-mdm2
EC 2.3.2.27
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1167-1181Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL056067
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI034495
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 by The American Society of Hematology.
Références
Biol Blood Marrow Transplant. 2020 Aug;26(8):e177-e182
pubmed: 32438042
Bone Marrow Transplant. 2017 May;52(5):678-682
pubmed: 28112748
Nat Commun. 2013;4:2359
pubmed: 23965983
Exp Cell Res. 2012 Jul 1;318(11):1269-77
pubmed: 22542855
Blood Adv. 2022 Jan 11;6(1):87-99
pubmed: 34535017
Clin Cancer Res. 2022 Mar 01;28(5):870-881
pubmed: 34862243
Nat Med. 2014 Jun;20(6):648-54
pubmed: 24836575
Blood. 2019 Mar 21;133(12):1290-1297
pubmed: 30578254
Sci Transl Med. 2020 Oct 28;12(567):
pubmed: 33115954
Blood. 2013 Nov 21;122(22):3607-15
pubmed: 24046014
J Exp Med. 2008 Aug 4;205(8):1929-38
pubmed: 18663127
Nat Med. 2018 Mar;24(3):282-291
pubmed: 29431743
Cancer Cell. 2002 Jul;2(1):9-15
pubmed: 12150820
Eur J Haematol. 2016 Mar;96(3):236-44
pubmed: 25912052
Blood. 2005 Nov 1;106(9):3150-9
pubmed: 16014563
N Engl J Med. 2009 Jul 30;361(5):478-88
pubmed: 19641204
Leukemia. 2012 Jul;26(7):1617-29
pubmed: 22301676
Nat Med. 2019 Apr;25(4):603-611
pubmed: 30911134
Science. 2004 Feb 6;303(5659):844-8
pubmed: 14704432
Cancer Discov. 2022 Jun 2;12(6):1449-1461
pubmed: 35255120
Bone Marrow Transplant. 2022 Jan;57(1):116-118
pubmed: 34611291
Nat Med. 1999 Feb;5(2):157-63
pubmed: 9930862
J Immunol. 2003 May 15;170(10):4986-95
pubmed: 12734342
Blood Adv. 2021 Dec 14;5(23):5047-5056
pubmed: 34607341
N Engl J Med. 2013 May 30;368(22):2059-74
pubmed: 23634996
N Engl J Med. 2016 Jun 9;374(23):2209-2221
pubmed: 27276561
Blood Adv. 2020 Oct 27;4(20):5011-5024
pubmed: 33057635
J Clin Oncol. 2007 Nov 1;25(31):4938-45
pubmed: 17909197
Nat Commun. 2021 Nov 8;12(1):6436
pubmed: 34750374
J Clin Oncol. 2020 Sep 10;38(26):2993-3002
pubmed: 32673171
Nature. 2018 Oct;562(7728):526-531
pubmed: 30333627
Blood Adv. 2021 Nov 23;5(22):4701-4709
pubmed: 34432868
Biol Blood Marrow Transplant. 2019 Apr;25(4):e128-e140
pubmed: 30658222
Cancer Res. 2013 Apr 15;73(8):2587-97
pubmed: 23400593
Nat Immunol. 2021 Apr;22(4):460-470
pubmed: 33767425
Bone Marrow Transplant. 2022 May;57(5):775-780
pubmed: 35228711
Sci Transl Med. 2020 Jun 3;12(546):
pubmed: 32493790
Biol Blood Marrow Transplant. 2014 Dec;20(12):2042-8
pubmed: 25239228
Cancer Discov. 2021 Dec 1;11(12):3090-3105
pubmed: 34230007
Ann Hematol. 2022 Jan;101(1):119-130
pubmed: 34568973
Genes Dev. 2011 Aug 15;25(16):1746-57
pubmed: 21852537
J Immunol. 2011 Jan 1;186(1):359-71
pubmed: 21135165
N Engl J Med. 2016 Jul 14;375(2):143-53
pubmed: 27410923
N Engl J Med. 2018 Dec 13;379(24):2330-2341
pubmed: 30380364
Nat Med. 2010 Dec;16(12):1434-8
pubmed: 21102458
Eur Rev Med Pharmacol Sci. 2014;18(4):537-43
pubmed: 24615181
Immunology. 2004 Nov;113(3):363-70
pubmed: 15500623