A High-avidity WT1-reactive T-Cell Receptor Mediates Recognition of Peptide and Processed Antigen but not Naturally Occurring WT1-positive Tumor Cells
| Autor: | Adnan Jaigirdar, Maria R. Parkhurst, Steven A. Rosenberg |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Cancer Research congenital hereditary and neonatal diseases and abnormalities medicine.medical_treatment T cell Receptors Antigen T-Cell alpha-beta Immunology Receptors Antigen T-Cell Epitopes T-Lymphocyte Gene Expression Human leukocyte antigen Biology urologic and male genital diseases Epitope Article 03 medical and health sciences 0302 clinical medicine Antigen Cancer immunotherapy Antigens Neoplasm T-Lymphocyte Subsets Cell Line Tumor Neoplasms HLA-A2 Antigen medicine Immunology and Allergy Animals Humans Cloning Molecular WT1 Proteins Pharmacology Antigen Presentation Leukemia Antigen processing urogenital system T-cell receptor fungi Immunotherapy female genital diseases and pregnancy complications 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer research |
| Zdroj: | Journal of immunotherapy (Hagerstown, Md. : 1997). 39(3) |
| ISSN: | 1537-4513 |
| Popis: | Wilms tumor gene 1 (WT1) is an attractive target antigen for cancer immunotherapy because it is overexpressed in many hematologic malignancies and solid tumors but has limited, low-level expression in normal adult tissues. Multiple HLA class I and class II restricted epitopes have been identified in WT1, and multiple investigators are pursuing the treatment of cancer patients with WT1-based vaccines and adoptively transferred WT1-reactive T cells. Here we isolated an HLA-A*0201-restricted WT1-reactive T-cell receptor (TCR) by stimulating peripheral blood lymphocytes of healthy donors with the peptide WT1:126-134 in vitro. This TCR mediated peptide recognition down to a concentration of ∼0.1 ng/mL when pulsed onto T2 cells as well as recognition of HLA-A*0201 target cells transfected with full-length WT1 cDNA. However, it did not mediate consistent recognition of many HLA-A*0201 tumor cell lines or freshly isolated leukemia cells that endogeneously expressed WT1. We dissected this pattern of recognition further and observed that WT1:126-134 was more efficiently processed by immunoproteasomes compared with standard proteasomes. However, pretreatment of WT1 tumor cell lines with interferon gamma did not appreciably enhance recognition by our TCR. In addition, we highly overexpressed WT1 in several leukemia cell lines by electroporation with full-length WT1 cDNA. Some of these lines were still not recognized by our TCR suggesting possible antigen processing defects in some leukemias. These results suggest WT1:126-134 may not be a suitable target for T-cell based tumor immunotherapies. |
| Databáze: | OpenAIRE |
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