B-cell-specific IRF4 deletion accelerates chronic lymphocytic leukemia development by enhanced tumor immune evasion.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
14 11 2019
14 11 2019
Historique:
received:
01
04
2019
accepted:
03
09
2019
pubmed:
21
9
2019
medline:
3
3
2020
entrez:
21
9
2019
Statut:
ppublish
Résumé
Chronic lymphocytic leukemia (CLL) is a heterogenous disease that is highly dependent on a cross talk of CLL cells with the microenvironment, in particular with T cells. T cells derived from CLL patients or murine CLL models are skewed to an antigen-experienced T-cell subset, indicating a certain degree of antitumor recognition, but they are also exhausted, preventing an effective antitumor immune response. Here we describe a novel mechanism of CLL tumor immune evasion that is independent of T-cell exhaustion, using B-cell-specific deletion of the transcription factor IRF4 (interferon regulatory factor 4) in Tcl-1 transgenic mice developing a murine CLL highly similar to the human disease. We show enhanced CLL disease progression in IRF4-deficient Tcl-1 tg mice, associated with a severe downregulation of genes involved in T-cell activation, including genes involved in antigen processing/presentation and T-cell costimulation, which massively reduced T-cell subset skewing and exhaustion. We found a strong analogy in the human disease, with inferior prognosis of CLL patients with low IRF4 expression in independent CLL patient cohorts, failed T-cell skewing to antigen-experienced subsets, decreased costimulation capacity, and downregulation of genes involved in T-cell activation. These results have therapeutic relevance because our findings on molecular mechanisms of immune privilege may be responsible for the failure of immune-therapeutic strategies in CLL and may lead to improved targeting in the future.
Identifiants
pubmed: 31537531
pii: S0006-4971(20)73980-7
doi: 10.1182/blood.2019000973
pmc: PMC6895374
doi:
Substances chimiques
Interferon Regulatory Factors
0
interferon regulatory factor-4
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1717-1729Subventions
Organisme : Austrian Science Fund FWF
ID : I 2795
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : I 3282
Pays : Austria
Informations de copyright
© 2019 by The American Society of Hematology.
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