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Experimental Therapeutics, Preclinical Pharmacology |
1 First Department of Surgery, and 2 Department of Neurosurgery, University of Yamanashi, Yamanashi, Japan
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.
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