PMID- 20865050
OWN - NLM
STAT- MEDLINE
DCOM- 20110113
LR  - 20211020
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 5
IP  - 8
DP  - 2010 Aug 26
TI  - Trastuzumab mediated T-cell response against HER-2/neu overexpressing esophageal 
      adenocarcinoma depends on intact antigen processing machinery.
PG  - e12424
LID - e12424 [pii]
LID - 10.1371/journal.pone.0012424 [doi]
AB  - BACKGROUND: Esophageal adenocarcinoma (EAC) is a highly aggressive disease with 
      poor prognosis, which frequently exhibits HER-2 gene amplification. Trastuzumab, 
      the humanized antibody against HER-2, has potent growth inhibitory effects on 
      HER-2 overexpressing cancers. One effect of trastuzumab is that it causes HER-2 
      receptor internalization and degradation, enhancing presentation of HER-2 
      epitopes on MHC-Class I molecules. This enhances the ability of HER-2 specific 
      cytotoxic T lymphocytes (CTLs) to recognize and kill cancer cells. Novel 
      strategies targeting the HER-2 receptor either directly by trastuzumab and/or 
      indirectly by inducing a CTL response against HER-2 epitopes with, for instance, 
      DC immunotherapy and consequently combining these strategies might prove to be 
      very effective. METHODOLOGY/PRINCIPAL FINDINGS: In this study we report that 
      trastuzumab has potent growth inhibitory effects on two HER-2 overexpressing EAC 
      cell lines OE33 and OE19. However, we found that trastuzumab and HER-2 specific 
      CTLs act synergistically in inducing tumor lysis in OE33 but not in OE19. We 
      discovered that in OE19 this deficient response is due to a down-regulation of 
      the Transporter Associated with Antigen Processing-2 (TAP-2). TAP-2 is an 
      important member of the Antigen Processing Machinery (APM), and is one of the 
      essential elements for loading antigens on MHC class I molecules. Importantly, we 
      demonstrated that by inducing re-expression of TAP-2 in OE19 with INF-gamma treatment 
      or by incubating the cells with INF-gamma producing CTLs, the specific anti HER-2 CTL 
      tumor lysis response and synergistic effect with trastuzumab can be restored. 
      CONCLUSION: An inefficient response of HER-2 overexpressing EAC to trastuzumab 
      and/or DC immunotherapy can be due to a down-regulated TAP-2 expression and thus 
      a deficient APM. Future studies combining trastuzumab with IFN-gamma and/or 
      immune-therapies inducing potent anti HER-2 CTL responses could lead to an 
      effective combinatorial strategy for successful treatment of HER-2 overexpressing 
      but APM defective cancers.
FAU - Milano, Francesca
AU  - Milano F
AD  - Center of Experimental and Molecular Medicine, Academic Medical Center, 
      Amsterdam, The Netherlands. F.Milano@amc.uva.nl
FAU - Guarriera, Mirta
AU  - Guarriera M
FAU - Rygiel, Agnieszka M
AU  - Rygiel AM
FAU - Krishnadath, Kausilia K
AU  - Krishnadath KK
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100826
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 3)
RN  - 0 (ATP-Binding Cassette Transporters)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 145892-13-3 (TAP2 protein, human)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
RN  - P188ANX8CK (Trastuzumab)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 3
MH  - ATP-Binding Cassette Transporters/genetics/*immunology
MH  - Adenocarcinoma/drug therapy/genetics/*immunology
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies, Monoclonal/*pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Antigen Presentation/*drug effects
MH  - Cell Line, Tumor
MH  - Cells, Cultured
MH  - Esophageal Neoplasms/drug therapy/genetics/*immunology
MH  - Gene Expression/*drug effects
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Receptor, ErbB-2/*genetics/immunology
MH  - T-Lymphocytes/drug effects/*immunology
MH  - Trastuzumab
PMC - PMC2928738
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2010/09/25 06:00
MHDA- 2011/01/14 06:00
PMCR- 2010/08/26
CRDT- 2010/09/25 06:00
PHST- 2010/03/12 00:00 [received]
PHST- 2010/08/03 00:00 [accepted]
PHST- 2010/09/25 06:00 [entrez]
PHST- 2010/09/25 06:00 [pubmed]
PHST- 2011/01/14 06:00 [medline]
PHST- 2010/08/26 00:00 [pmc-release]
AID - e12424 [pii]
AID - 10-PONE-RA-17000R1-A [pii]
AID - 10.1371/journal.pone.0012424 [doi]
PST - epublish
SO  - PLoS One. 2010 Aug 26;5(8):e12424. doi: 10.1371/journal.pone.0012424.