PMID- 36054818
OWN - NLM
STAT- MEDLINE
DCOM- 20221024
LR  - 20230110
IS  - 1097-0215 (Electronic)
IS  - 0020-7136 (Print)
IS  - 0020-7136 (Linking)
VI  - 151
IP  - 12
DP  - 2022 Dec 15
TI  - The immunosuppression pathway of tumor-associated macrophages is controlled by 
      heme oxygenase-1 in glioblastoma patients.
PG  - 2265-2277
LID - 10.1002/ijc.34270 [doi]
AB  - The immunosuppressive tumor microenvironment (TME) in glioblastoma (GBM) is 
      mainly driven by tumor-associated macrophages (TAMs). We explored whether their 
      sustained iron metabolism and immunosuppressive activity were correlated, and 
      whether blocking the central enzyme of the heme catabolism pathway, heme 
      oxygenase-1 (HO-1), could reverse their tolerogenic activity. To this end, we 
      investigated iron metabolism in bone marrow-derived macrophages (BMDMs) isolated 
      from GBM specimens and in in vitro-derived macrophages (Mphi) from healthy donor 
      (HD) blood monocytes. We found that HO-1 inhibition abrogated the 
      immunosuppressive activity of both BMDMs and Mphi, and that immunosuppression 
      requires both cell-to-cell contact and soluble factors, as HO-1 inhibition 
      abolished IL-10 release, and significantly reduced STAT3 activation as well as 
      PD-L1 expression. Interestingly, not only did HO-1 inhibition downregulate IDO1 
      and ARG-2 gene expression, but also reduced IDO1 enzymatic activity. Moreover, T 
      cell activation status affected PD-L1 expression and IDO1 activity, which were 
      upregulated in the presence of activated, but not resting, T cells. Our results 
      highlight the crucial role of HO-1 in the immunosuppressive activity of 
      macrophages in the GBM TME and demonstrate the feasibility of reprogramming them 
      as an alternative therapeutic strategy for restoring immune surveillance.
CI  - (c) 2022 The Authors. International Journal of Cancer published by John Wiley & 
      Sons Ltd on behalf of UICC.
FAU - Magri, Sara
AU  - Magri S
AUID- ORCID: 0000-0002-8884-5299
AD  - Department of Surgery, Oncology and Gastroenterology, University of Padova, 
      Padova, Italy.
FAU - Musca, Beatrice
AU  - Musca B
AD  - Immunology and Molecular Oncology, Veneto Institute of Oncology IOV-IRCCS, 
      Padova, Italy.
FAU - Pinton, Laura
AU  - Pinton L
AD  - Immunology and Molecular Oncology, Veneto Institute of Oncology IOV-IRCCS, 
      Padova, Italy.
FAU - Orecchini, Elena
AU  - Orecchini E
AD  - Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
FAU - Belladonna, Maria Laura
AU  - Belladonna ML
AD  - Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
FAU - Orabona, Ciriana
AU  - Orabona C
AD  - Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
FAU - Bonaudo, Camilla
AU  - Bonaudo C
AD  - Neurosurgery, Department of NEUROFARBA, University of Florence, University 
      Hospital of Careggi, Florence, Italy.
FAU - Volpin, Francesco
AU  - Volpin F
AD  - Neurosurgery Department, University Hospital of Padova, Padova, Italy.
FAU - Ciccarino, Pietro
AU  - Ciccarino P
AD  - Neurosurgery Department, University Hospital of Padova, Padova, Italy.
FAU - Baro, Valentina
AU  - Baro V
AD  - Academic Neurosurgery, Department of Neurosciences, University of Padova, Padova, 
      Italy.
FAU - Della Puppa, Alessandro
AU  - Della Puppa A
AUID- ORCID: 0000-0001-8058-092X
AD  - Neurosurgery, Department of NEUROFARBA, University of Florence, University 
      Hospital of Careggi, Florence, Italy.
FAU - Mandruzzato, Susanna
AU  - Mandruzzato S
AUID- ORCID: 0000-0002-0707-995X
AD  - Department of Surgery, Oncology and Gastroenterology, University of Padova, 
      Padova, Italy.
AD  - Immunology and Molecular Oncology, Veneto Institute of Oncology IOV-IRCCS, 
      Padova, Italy.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220915
PL  - United States
TA  - Int J Cancer
JT  - International journal of cancer
JID - 0042124
RN  - 0 (B7-H1 Antigen)
RN  - 42VZT0U6YR (Heme)
RN  - EC 1.14.14.18 (Heme Oxygenase-1)
RN  - 130068-27-8 (Interleukin-10)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.14.14.18 (HMOX1 protein, human)
SB  - IM
MH  - Humans
MH  - B7-H1 Antigen/metabolism
MH  - *Glioblastoma/pathology
MH  - Heme
MH  - *Heme Oxygenase-1/genetics/metabolism
MH  - Immunosuppression Therapy
MH  - Interleukin-10
MH  - Iron
MH  - Tumor Microenvironment
MH  - *Tumor-Associated Macrophages
PMC - PMC9825884
OTO - NOTNLM
OT  - glioblastoma
OT  - heme oxygenase-1
OT  - iron metabolism
OT  - macrophages
OT  - tumor microenvironment
COIS- The authors report that there are no competing interests to declare.
EDAT- 2022/09/03 06:00
MHDA- 2022/10/22 06:00
PMCR- 2023/01/08
CRDT- 2022/09/02 15:22
PHST- 2022/08/05 00:00 [revised]
PHST- 2022/05/23 00:00 [received]
PHST- 2022/08/11 00:00 [accepted]
PHST- 2022/09/03 06:00 [pubmed]
PHST- 2022/10/22 06:00 [medline]
PHST- 2022/09/02 15:22 [entrez]
PHST- 2023/01/08 00:00 [pmc-release]
AID - IJC34270 [pii]
AID - 10.1002/ijc.34270 [doi]
PST - ppublish
SO  - Int J Cancer. 2022 Dec 15;151(12):2265-2277. doi: 10.1002/ijc.34270. Epub 2022 
      Sep 15.