PMID- 21478334
OWN - NLM
STAT- MEDLINE
DCOM- 20111024
LR  - 20220410
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Linking)
VI  - 17
IP  - 13
DP  - 2011 Jul 1
TI  - Effector T-cell infiltration positively impacts survival of glioblastoma patients 
      and is impaired by tumor-derived TGF-beta.
PG  - 4296-308
LID - 10.1158/1078-0432.CCR-10-2557 [doi]
AB  - PURPOSE: In glioma-in contrast to various other cancers-the impact of 
      T-lymphocytes on clinical outcome is not clear. We investigated the clinical 
      relevance and regulation of T-cell infiltration in glioma. EXPERIMENTAL DESIGN: 
      T-cell subpopulations from entire sections of 93 WHO degrees II-IV gliomas were 
      computationally identified using markers CD3, CD8, and Foxp3; survival analysis 
      was then done on primary glioblastomas (pGBM). Endothelial cells expressing 
      cellular adhesion molecules (CAM) were similarly computationally quantified from 
      the same glioma tissues. Influence of prominent cytokines (as measured by ELISA 
      from 53 WHO degrees II-IV glioma lysates) on CAM-expression in GBM-isolated endothelial 
      cells was determined using flow cytometry. The functional relevance of the 
      cytokine-mediated CAM regulation was tested in a transmigration assay using 
      GBM-derived endothelial cells and autologous T-cells. RESULTS: Infiltration of 
      all T-cell subsets increased in high-grade tumors. Most strikingly, within pGBM, 
      elevated numbers of intratumoral effector T cells (T(eff), cytotoxic and helper) 
      significantly correlated with a better survival; regulatory T cells were 
      infrequently present and not associated with GBM patient outcome. Interestingly, 
      increased infiltration of T(eff) cells was related to the expression of ICAM-1 on 
      the vessel surface. Transmigration of autologous T cells in vitro was markedly 
      reduced in the presence of CAM-blocking antibodies. We found that TGF-beta molecules 
      impeded transmigration and downregulated CAM-expression on GBM-isolated 
      endothelial cells; blocking TGF-beta receptor signaling increased transmigration. 
      CONCLUSIONS: This study provides comprehensive and novel insights into occurrence 
      and regulation of T-cell infiltration in glioma. Specifically, targeting TGF-beta1 
      and TGF-beta2 might improve intratumoral T-cell infiltration and thus enhance 
      effectiveness of immunotherapeutic approaches.
FAU - Lohr, Jennifer
AU  - Lohr J
AD  - Division of Neurosurgical Research, Department Neurosurgery, University of 
      Heidelberg, Heidelberg, Germany.
FAU - Ratliff, Thomas
AU  - Ratliff T
FAU - Huppertz, Andrea
AU  - Huppertz A
FAU - Ge, Yingzi
AU  - Ge Y
FAU - Dictus, Christine
AU  - Dictus C
FAU - Ahmadi, Rezvan
AU  - Ahmadi R
FAU - Grau, Stefan
AU  - Grau S
FAU - Hiraoka, Nobuyoshi
AU  - Hiraoka N
FAU - Eckstein, Volker
AU  - Eckstein V
FAU - Ecker, Rupert C
AU  - Ecker RC
FAU - Korff, Thomas
AU  - Korff T
FAU - von Deimling, Andreas
AU  - von Deimling A
FAU - Unterberg, Andreas
AU  - Unterberg A
FAU - Beckhove, Philipp
AU  - Beckhove P
FAU - Herold-Mende, Christel
AU  - Herold-Mende C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110408
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Angiogenesis Inducing Agents)
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Immunologic Factors)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Angiogenesis Inducing Agents/metabolism
MH  - Cell Adhesion Molecules/metabolism
MH  - Cell Movement/drug effects
MH  - Disease Progression
MH  - Down-Regulation/genetics
MH  - Endothelial Cells/immunology/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Glioblastoma/*immunology/metabolism/*mortality
MH  - Humans
MH  - Immunologic Factors/immunology/pharmacology
MH  - Lymphocytes, Tumor-Infiltrating/*immunology/metabolism
MH  - Protein Kinase Inhibitors/pharmacology
MH  - Receptors, Transforming Growth Factor beta/antagonists & inhibitors
MH  - Signal Transduction/drug effects
MH  - Survival Analysis
MH  - T-Lymphocytes/*immunology/metabolism
MH  - Transforming Growth Factor beta/*immunology/pharmacology
EDAT- 2011/04/12 06:00
MHDA- 2011/10/25 06:00
CRDT- 2011/04/12 06:00
PHST- 2011/04/12 06:00 [entrez]
PHST- 2011/04/12 06:00 [pubmed]
PHST- 2011/10/25 06:00 [medline]
AID - 1078-0432.CCR-10-2557 [pii]
AID - 10.1158/1078-0432.CCR-10-2557 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2011 Jul 1;17(13):4296-308. doi: 10.1158/1078-0432.CCR-10-2557. 
      Epub 2011 Apr 8.