Trastuzumab (Herceptin) Enhances Class I-Restricted Antigen Presentation Recognized by HER-2/neu-Specific T Cytotoxic Lymphocytes

• Published in: Clinical cancer research Vol. 10; no. 7; pp. 2538 - 2544
• Main Authors: KONO, Koji, SATO, Eiji, NAGANUMA, Hirofumi, TAKAHASHI, Akihiro, MIMURA, Kousaku, NUKUI, Hideaki, FUJII, Hideki
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.04.2004
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - therapeutic use; Annexin A5 - pharmacology; Antibodies, Monoclonal - chemistry; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antigens, Neoplasm - chemistry; Antineoplastic agents; Antineoplastic Agents - therapeutic use; Apoptosis; Biological and medical sciences; Blotting, Western; Cell Line, Tumor; Coloring Agents - pharmacology; Cytotoxicity, Immunologic; Enzyme-Linked Immunosorbent Assay; Epitopes; Flow Cytometry; Genes, MHC Class I; Histocompatibility Antigens Class I - chemistry; Humans; Medical sciences; Pharmacology. Drug treatments; Proteasome Endopeptidase Complex - metabolism; Proteasome Inhibitors; Receptor, ErbB-2 - immunology; T-Lymphocytes, Cytotoxic - immunology; Trastuzumab; Tumors; Antigen presentation; Cytotoxicity; Monoclonal antibody; Cytotoxic T lymphocyte; C-Onc gene; Trastuzumab
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-03-0424

Purpose: 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. Experimental Design: 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.