PMID- 37827154
OWN - NLM
STAT- MEDLINE
DCOM- 20240130
LR  - 20240212
IS  - 2666-3791 (Electronic)
IS  - 2666-3791 (Linking)
VI  - 4
IP  - 11
DP  - 2023 Nov 21
TI  - Genetic and pharmaceutical targeting of HIF1alpha allows combo-immunotherapy to boost 
      graft vs. leukemia without exacerbation graft vs. host disease.
PG  - 101236
LID - S2666-3791(23)00413-5 [pii]
LID - 10.1016/j.xcrm.2023.101236 [doi]
LID - 101236
AB  - 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 1alpha (HIF1alpha) 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 HIF1alpha 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.
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Bailey, Christopher
AU  - Bailey C
AD  - Division of Immunotherapy, Institute of Human Virology, Department of Surgery and 
      Comprehensive Cancer Center, University of Maryland School of Medicine, 
      Baltimore, MD 21201, USA.
FAU - Wei, Yuanyi
AU  - Wei Y
AD  - Division of Immunotherapy, Institute of Human Virology, Department of Surgery and 
      Comprehensive Cancer Center, University of Maryland School of Medicine, 
      Baltimore, MD 21201, USA.
FAU - Yan, Jinsong
AU  - Yan J
AD  - Department of Hematology, The Second Hospital of Dalian Medical University, 
      Dalian, China.
FAU - Huang, Dan
AU  - Huang D
AD  - Department of Hematology, The Second Hospital of Dalian Medical University, 
      Dalian, China.
FAU - Zhang, Peng
AU  - Zhang P
AD  - Department of Neurosurgery, Beijing Children's Hospital, Capital Medical 
      University, National Cancer for Children's Health, Beijing, China.
FAU - Qi, Chong
AU  - Qi C
AD  - Institute of Translational Medicine, The First Hospital, Jilin University, 
      Changchun, Jilin 130061, China.
FAU - Lazarski, Christopher
AU  - Lazarski C
AD  - Center for Cancer and Immunology Research, Children's Research Institute, 
      Washington, DC 20010, USA.
FAU - Su, JuanJuan
AU  - Su J
AD  - Division of Immunotherapy, Institute of Human Virology, Department of Surgery and 
      Comprehensive Cancer Center, University of Maryland School of Medicine, 
      Baltimore, MD 21201, USA.
FAU - Tang, Fei
AU  - Tang F
AD  - Division of Immunotherapy, Institute of Human Virology, Department of Surgery and 
      Comprehensive Cancer Center, University of Maryland School of Medicine, 
      Baltimore, MD 21201, USA.
FAU - Wong, Chun-Shu
AU  - Wong CS
AD  - Center for Cancer and Immunology Research, Children's Research Institute, 
      Washington, DC 20010, USA.
FAU - Zheng, Pan
AU  - Zheng P
AD  - Division of Immunotherapy, Institute of Human Virology, Department of Surgery and 
      Comprehensive Cancer Center, University of Maryland School of Medicine, 
      Baltimore, MD 21201, USA; OncoC4, Inc., Rockville, MD 20852, USA.
FAU - Liu, Yan
AU  - Liu Y
AD  - Division of Immunotherapy, Institute of Human Virology, Department of Surgery and 
      Comprehensive Cancer Center, University of Maryland School of Medicine, 
      Baltimore, MD 21201, USA. Electronic address: yanliu@ihv.umaryland.edu.
FAU - Liu, Yang
AU  - Liu Y
AD  - Division of Immunotherapy, Institute of Human Virology, Department of Surgery and 
      Comprehensive Cancer Center, University of Maryland School of Medicine, 
      Baltimore, MD 21201, USA; OncoC4, Inc., Rockville, MD 20852, USA. Electronic 
      address: yangl@oncoc4.com.
FAU - Wang, Yin
AU  - Wang Y
AD  - Division of Immunotherapy, Institute of Human Virology, Department of Surgery and 
      Comprehensive Cancer Center, University of Maryland School of Medicine, 
      Baltimore, MD 21201, USA. Electronic address: yin.wang@ihv.umaryland.edu.
LA  - eng
GR  - R01 CA171972/CA/NCI NIH HHS/United States
GR  - R01 CA219150/CA/NCI NIH HHS/United States
GR  - R01 CA227671/CA/NCI NIH HHS/United States
GR  - U01 CA183030/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20231011
PL  - United States
TA  - Cell Rep Med
JT  - Cell reports. Medicine
JID - 101766894
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
SB  - IM
MH  - Humans
MH  - CTLA-4 Antigen
MH  - *Graft vs Host Disease/prevention & control
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Immunotherapy
MH  - *Leukemia/genetics/therapy
MH  - Animals
MH  - Mice
PMC - PMC10694596
OTO - NOTNLM
OT  - bone marrow transplantation
OT  - cytotoxic T-lymphocyte associated protein 4
OT  - graft vs. host disease
OT  - graft vs. leukemia
OT  - hypoxia-inducible factor 1alpha
OT  - immune checkpoint inhibitor
OT  - immunotherapy-related adverse events
OT  - programmed Cell Death 1
OT  - programmed death ligand 1
COIS- Declaration of interests Yang Liu and Pan Zheng are among the co-founders of and 
      have equity interest in OncoC4, Inc.
EDAT- 2023/10/13 00:43
MHDA- 2023/11/24 06:42
PMCR- 2023/10/11
CRDT- 2023/10/12 18:42
PHST- 2023/04/17 00:00 [received]
PHST- 2023/07/27 00:00 [revised]
PHST- 2023/09/20 00:00 [accepted]
PHST- 2023/11/24 06:42 [medline]
PHST- 2023/10/13 00:43 [pubmed]
PHST- 2023/10/12 18:42 [entrez]
PHST- 2023/10/11 00:00 [pmc-release]
AID - S2666-3791(23)00413-5 [pii]
AID - 101236 [pii]
AID - 10.1016/j.xcrm.2023.101236 [doi]
PST - ppublish
SO  - Cell Rep Med. 2023 Nov 21;4(11):101236. doi: 10.1016/j.xcrm.2023.101236. Epub 
      2023 Oct 11.