PMID- 21948231
OWN - NLM
STAT- MEDLINE
DCOM- 20120325
LR  - 20220318
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 17
IP  - 22
DP  - 2011 Nov 15
TI  - Neutrophil degranulation and immunosuppression in patients with GBM: restoration 
      of cellular immune function by targeting arginase I.
PG  - 6992-7002
LID - 10.1158/1078-0432.CCR-11-1107 [doi]
AB  - PURPOSE: The source of glioblastoma (GBM)-associated immunosuppression remains 
      multifactorial. We sought to clarify and therapeutically target myeloid 
      cell-derived peripheral immunosuppression in patients with GBM. EXPERIMENTAL 
      DESIGN: Direct ex vivo T-cell function, serum Arginase I (ArgI) levels, and 
      circulating myeloid lineage populations were compared between patients with GBM 
      and normal donors or patients with other intracranial tumors. Immunofunctional 
      assays were conducted using bulk and sorted cell populations to explore the 
      potential transfer of myeloid cell-mediated immunosuppression and to identify a 
      potential mechanism for these effects. ArgI-mediated immunosuppression was 
      therapeutically targeted in vitro through pharmacologic inhibition or arginine 
      supplementation. RESULTS: We identified a significantly expanded population of 
      circulating, degranulated neutrophils associated with elevated levels of serum 
      ArgI and decreased T-cell CD3zeta expression within peripheral blood from patients 
      with GBM. Sorted CD11b(+) cells from patients with GBM were found to markedly 
      suppress normal donor T-cell function in coculture, and media harvested from 
      mitogen-stimulated GBM peripheral blood mononuclear cell (PBMC) or GBM-associated 
      mixed lymphoid reactions showed ArgI levels that were significantly higher than 
      controls. Critically, T-cell suppression in both settings could be completely 
      reversed through pharmacologic ArgI inhibition or with arginine supplementation. 
      CONCLUSIONS: These data indicate that peripheral cellular immunosuppression in 
      patients with GBM is associated with neutrophil degranulation and elevated levels 
      of circulating ArgI, and that T-cell function can be restored in these 
      individuals by targeting ArgI. These data identify a novel pathway of 
      GBM-mediated suppression of cellular immunity and offer a potential therapeutic 
      window for improving antitumor immunity in affected patients.
FAU - Sippel, Trisha R
AU  - Sippel TR
AD  - Department of Neurosurgery, University of Colorado Anschutz Medical Campus, 
      Aurora, Colorado 80045, USA.
FAU - White, Jason
AU  - White J
FAU - Nag, Kamalika
AU  - Nag K
FAU - Tsvankin, Vadim
AU  - Tsvankin V
FAU - Klaassen, Marci
AU  - Klaassen M
FAU - Kleinschmidt-DeMasters, B K
AU  - Kleinschmidt-DeMasters BK
FAU - Waziri, Allen
AU  - Waziri A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110926
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 94ZLA3W45F (Arginine)
RN  - EC 3.5.3.1 (Arginase)
SB  - IM
MH  - Arginase/antagonists & inhibitors/*physiology
MH  - Arginine/therapeutic use
MH  - Brain Neoplasms/*drug therapy/enzymology/*immunology
MH  - *Cell Degranulation
MH  - Cells, Cultured
MH  - Glioblastoma/*drug therapy/enzymology/*immunology
MH  - Humans
MH  - *Immune Tolerance
MH  - Immunity, Cellular
MH  - Molecular Targeted Therapy/*methods
MH  - Neutrophils/*immunology
MH  - T-Lymphocytes/immunology
EDAT- 2011/09/29 06:00
MHDA- 2012/03/27 06:00
CRDT- 2011/09/28 06:00
PHST- 2011/09/28 06:00 [entrez]
PHST- 2011/09/29 06:00 [pubmed]
PHST- 2012/03/27 06:00 [medline]
AID - 1078-0432.CCR-11-1107 [pii]
AID - 10.1158/1078-0432.CCR-11-1107 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2011 Nov 15;17(22):6992-7002. doi: 
      10.1158/1078-0432.CCR-11-1107. Epub 2011 Sep 26.