Genetic and pharmaceutical targeting of HIF1α allows combo-immunotherapy to boost graft vs. leukemia without exacerbation graft vs. host disease.
bone marrow transplantation
cytotoxic T-lymphocyte associated protein 4
graft vs. host disease
graft vs. leukemia
hypoxia-inducible factor 1α
immune checkpoint inhibitor
immunotherapy-related adverse events
programmed Cell Death 1
programmed death ligand 1
Journal
Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894
Informations de publication
Date de publication:
21 Nov 2023
21 Nov 2023
Historique:
received:
17
04
2023
revised:
27
07
2023
accepted:
20
09
2023
medline:
24
11
2023
pubmed:
13
10
2023
entrez:
12
10
2023
Statut:
ppublish
Résumé
Despite potential impact on the graft vs. leukemia (GVL) effect, immunotherapy targeting CTLA-4 and/or PD-1 has not been successfully combined with bone marrow transplant (BMT) because it exacerbates graft vs. host disease (GVHD). Here, using models of GVHD and leukemia, we demonstrate that targeting hypoxia-inducible factor 1α (HIF1α) via pharmacological or genetic approaches reduces GVHD by inducing PDL1 expression on host tissue while selectively inhibiting PDL1 in leukemia cells to enhance the GVL effect. More importantly, combination of HIF1α inhibition with anti-CTLA-4 antibodies allows simultaneous inhibition of both PDL1 and CTLA-4 checkpoints to achieve better outcomes in models of mouse and human BMT-leukemia settings. These findings provide an approach to enhance the curative effect of BMT for leukemia and broaden the impact of cancer immunotherapy.
Identifiants
pubmed: 37827154
pii: S2666-3791(23)00413-5
doi: 10.1016/j.xcrm.2023.101236
pmc: PMC10694596
pii:
doi:
Substances chimiques
CTLA-4 Antigen
0
Pharmaceutical Preparations
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
101236Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests Yang Liu and Pan Zheng are among the co-founders of and have equity interest in OncoC4, Inc.
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