Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation.
Gene Expression Profiling
Gene Expression Regulation, Leukemic
Hematopoietic Stem Cell Transplantation
Histocompatibility Antigens Class II
/ genetics
Humans
Leukemia, Myeloid, Acute
/ genetics
Lymphocyte Activation
/ immunology
RNA, Messenger
/ genetics
Recurrence
Reproducibility of Results
Transplantation, Homologous
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
15
03
2018
accepted:
15
02
2019
pubmed:
27
3
2019
medline:
11
5
2019
entrez:
27
3
2019
Statut:
ppublish
Résumé
Transplantation of hematopoietic cells from a healthy individual (allogeneic hematopoietic cell transplantation (allo-HCT)) demonstrates that adoptive immunotherapy can cure blood cancers: still, post-transplantation relapses remain frequent. To explain their drivers, we analyzed the genomic and gene expression profiles of acute myeloid leukemia (AML) blasts purified from patients at serial time-points during their disease history. We identified a transcriptional signature specific for post-transplantation relapses and highly enriched in immune-related processes, including T cell costimulation and antigen presentation. In two independent patient cohorts we confirmed the deregulation of multiple costimulatory ligands on AML blasts at post-transplantation relapse (PD-L1, B7-H3, CD80, PVRL2), mirrored by concomitant changes in circulating donor T cells. Likewise, we documented the frequent loss of surface expression of HLA-DR, -DQ and -DP on leukemia cells, due to downregulation of the HLA class II regulator CIITA. We show that loss of HLA class II expression and upregulation of inhibitory checkpoint molecules represent alternative modalities to abolish AML recognition from donor-derived T cells, and can be counteracted by interferon-γ or checkpoint blockade, respectively. Our results demonstrate that the deregulation of pathways involved in T cell-mediated allorecognition is a distinctive feature and driver of AML relapses after allo-HCT, which can be rapidly translated into personalized therapies.
Identifiants
pubmed: 30911134
doi: 10.1038/s41591-019-0400-z
pii: 10.1038/s41591-019-0400-z
doi:
Substances chimiques
Histocompatibility Antigens Class II
0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
603-611Références
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