Trastuzumab (Herceptin) enhances class I-restricted antigen presentation recognized by HER-2/neu-specific T cytotoxic lymphocytes.
OBJECTIVE
Numerous examples from animal models and clinical trials showed that HER-2-derived peptides are naturally processed as a CTL epitope and can be recognized by tumor-specific CTLs in several tumors with HER-2 overexpression. The humanized anti-HER-2 monoclonal antibody, Herceptin, has been designed to specifically antagonize the HER-2 function by directing against the extracellular domain of the HER-2 protein. One of the actions of Herceptin includes the internalization and degradation of HER-2, which might increase the amount of HER-2-derived peptides available for loading to MHC class I.


METHODS
In the present study, we investigated how Herceptin treatment of HER-2-overexpressing targets affects lysis by HER-2-specific CTLs.


RESULTS
We showed that Herceptin sensitized HER-2-overexpressing tumors to lysis by HLA-A2-restricted or HLA-A24-restricted CTLs, without any effect of the expression of MHC class I, costimulatory molecules, adhesion molecules, or TAP-1 on the targets. Furthermore, the enhancement of cytolytic activity with Herceptin was inhibited by addition of a specific proteasome inhibitor, lactacystin.


CONCLUSIONS
These results suggested that Herceptin treatment might enhance the class I-restricted presentation of endogenous HER-2 antigen via the proteasome step, resulting in higher susceptibility of HER-2-overexpressing tumors to lysis by the HER-2-specific CTLs.
Kono
Koji
K
First Department of Surgery, and Department of Neurosurgery, University of Yamanashi, Yamanashi, Japan. kojikono@yamanashi.ac.jp
Sato
Eiji
E
Naganuma
Hirofumi
H
Takahashi
Akihiro
A
Mimura
Kousaku
K
Nukui
Hideaki
H
Fujii
Hideki
H
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D017304:Annexin A5 / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm / Q000737:chemistry; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004396:Coloring Agents / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005434:Flow Cytometry; D005805:Genes, MHC Class I; D015395:Histocompatibility Antigens Class I / Q000737:chemistry; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000068878:Trastuzumab
D000111:Acetylcysteine; D017304:Annexin A5; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004396:Coloring Agents; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D046988:Proteasome Endopeptidase Complex; D061988:Proteasome Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C067713:lactacystin