PMID- 23363816
OWN - NLM
STAT- MEDLINE
DCOM- 20130930
LR  - 20211021
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 19
IP  - 4
DP  - 2013 Feb 15
TI  - SHP2 is overexpressed and inhibits pSTAT1-mediated APM component expression, 
      T-cell attracting chemokine secretion, and CTL recognition in head and neck 
      cancer cells.
PG  - 798-808
LID - 10.1158/1078-0432.CCR-12-1517 [doi]
AB  - PURPOSE: Human leukocyte antigen (HLA) class I antigen processing machinery (APM) 
      component downregulation permits escape of malignant cells from recognition by 
      cytotoxic T lymphocytes (CTL) and correlates with poor prognosis in patients with 
      head and neck cancer (HNC). Activated STAT1 (pSTAT1) is necessary for APM 
      component expression in HNC cells. We investigated whether an overexpressed 
      phosphatase was responsible for basal suppression of pSTAT1 and subsequent APM 
      component-mediated immune escape in HNC cells. EXPERIMENTAL DESIGN: 
      Immunohistochemical staining and reverse transcription PCR of paired HNC tumors 
      was performed for the phosphatases src homology domain-containing phosphatase 
      (SHP)-1 and SHP2. Depletion of phosphatase activity in HNC and STAT1(-/-) tumor 
      cells was achieved by siRNA knockdown. HLA class I-restricted, tumor 
      antigen-specific CTL were used in IFN-gamma ELISPOT assays against HNC cells. 
      Chemokine secretion was measured after SHP2 depletion in HNC cells. RESULTS: 
      SHP2, but not SHP1, was significantly upregulated in HNC tissues. In HNC cells, 
      SHP2 depletion significantly upregulated expression of pSTAT1 and HLA class I APM 
      components. Overexpression of SHP2 in nonmalignant keratinocytes inhibited 
      IFN-gamma-mediated STAT1 phosphorylation, and SHP2 depletion in STAT1(-/-) tumor 
      cells did not significantly induce IFN-gamma-mediated APM component expression, 
      verifying STAT1 dependence of SHP2 activity. SHP2 depletion induced recognition 
      of HNC cells by HLA class I-restricted CTL and secretion of inflammatory, T-cell 
      attracting chemokines, RANTES and IP10. CONCLUSION: These findings suggest for 
      the first time an important role for SHP2 in APM-mediated escape of HNC cells 
      from CTL recognition. Targeting SHP2 could enhance T-cell-based cancer 
      immunotherapy.
CI  - (c)2012 AACR.
FAU - Leibowitz, Michael S
AU  - Leibowitz MS
AD  - Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
FAU - Srivastava, Raghvendra M
AU  - Srivastava RM
FAU - Andrade Filho, Pedro A
AU  - Andrade Filho PA
FAU - Egloff, Ann Marie
AU  - Egloff AM
FAU - Wang, Lin
AU  - Wang L
FAU - Seethala, Raja R
AU  - Seethala RR
FAU - Ferrone, Soldano
AU  - Ferrone S
FAU - Ferris, Robert L
AU  - Ferris RL
LA  - eng
GR  - R01 DE019727/DE/NIDCR NIH HHS/United States
GR  - R01 CA110249/CA/NCI NIH HHS/United States
GR  - CA110249/CA/NCI NIH HHS/United States
GR  - P50 CA097190/CA/NCI NIH HHS/United States
GR  - CA097190/CA/NCI NIH HHS/United States
GR  - P30 CA047904/CA/NCI NIH HHS/United States
GR  - DE019727/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130130
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 (HLA Antigens)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
RN  - 82115-62-6 (Interferon-gamma)
RN  - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11)
SB  - IM
MH  - Carcinoma, Squamous Cell/*genetics/pathology
MH  - Cell Line, Tumor
MH  - Down-Regulation
MH  - Gene Expression Regulation, Neoplastic
MH  - HLA Antigens/genetics/immunology/*metabolism
MH  - Head and Neck Neoplasms/*genetics/pathology
MH  - Humans
MH  - Interferon-gamma/genetics/metabolism
MH  - Keratinocytes
MH  - Phosphorylation
MH  - Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/*metabolism
MH  - RNA, Small Interfering
MH  - STAT1 Transcription Factor/genetics/*metabolism
MH  - T-Lymphocytes, Cytotoxic/metabolism
PMC - PMC3578140
MID - NIHMS431366
EDAT- 2013/02/01 06:00
MHDA- 2013/10/01 06:00
PMCR- 2014/02/15
CRDT- 2013/02/01 06:00
PHST- 2013/02/01 06:00 [entrez]
PHST- 2013/02/01 06:00 [pubmed]
PHST- 2013/10/01 06:00 [medline]
PHST- 2014/02/15 00:00 [pmc-release]
AID - 1078-0432.CCR-12-1517 [pii]
AID - 10.1158/1078-0432.CCR-12-1517 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2013 Feb 15;19(4):798-808. doi: 10.1158/1078-0432.CCR-12-1517. 
      Epub 2013 Jan 30.