1. Trastuzumab Mediated T-Cell Response against HER-2/Neu Overexpressing Esophageal Adenocarcinoma Depends on Intact Antigen Processing Machinery
- Author
-
Agnieszka M. Rygiel, Mirta Guarriera, Kausilia K. Krishnadath, Francesca Milano, Amsterdam Gastroenterology Endocrinology Metabolism, Cancer Center Amsterdam, Gastroenterology and Hepatology, Center of Experimental and Molecular Medicine, and Faculteit der Geneeskunde
- Subjects
Genetics and Molecular Biology (all) ,Male ,Esophageal Neoplasms ,Receptor, ErbB-2 ,medicine.medical_treatment ,T-Lymphocytes ,lcsh:Medicine ,Gene Expression ,Biochemistry ,ErbB-2 ,Trastuzumab ,Monoclonal ,80 and over ,Cytotoxic T cell ,lcsh:Science ,Humanized ,Cells, Cultured ,Aged, 80 and over ,Antigen Presentation ,Tumor ,Cultured ,Multidisciplinary ,Antigen processing ,Medicine (all) ,Antibodies, Monoclonal ,Middle Aged ,Oncology ,Immunology/Antigen Processing and Recognition ,Receptor ,medicine.drug ,Research Article ,ATP-Binding Cassette Transporters ,ATP-Binding Cassette, Sub-Family B, Member 3 ,Adenocarcinoma ,Aged ,Antibodies, Monoclonal, Humanized ,Cell Line, Tumor ,Humans ,Agricultural and Biological Sciences (all) ,Biochemistry, Genetics and Molecular Biology (all) ,Gastroenterology and Hepatology/Gastrointestinal Cancers ,Member 3 ,Cells ,Antigen presentation ,Immunology ,Oncology/Gastrointestinal Cancers ,Biology ,Antibodies ,Cell Line ,Antigen ,ATP Binding Cassette Transporter, Subfamily B, Member 3 ,MHC class I ,medicine ,Sub-Family B ,lcsh:R ,Immunotherapy ,CTL ,Immunology/Leukocyte Activation ,Immunology/Immune Response ,Cancer research ,biology.protein ,ATP-Binding Cassette ,lcsh:Q ,Gastroenterology and Hepatology/Esophagus - Abstract
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-c treatment or by incubating the cells with INF-c 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-c 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.
- Published
- 2010