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A High-avidity WT1-reactive T-Cell Receptor Mediates Recognition of Peptide and Processed Antigen but not Naturally Occurring WT1-positive Tumor Cells

Jaigirdar, Adnan; Rosenberg, Steven A.; Parkhurst, Maria

Journal of immunotherapy: official journal of the Society for Biological Therapy. Volume 39:Issue 3 (2016, April) -- Lippincott Williams & Wilkins

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  • Title:
    A High-avidity WT1-reactive T-Cell Receptor Mediates Recognition of Peptide and Processed Antigen but not Naturally Occurring WT1-positive Tumor Cells
  • Author: Jaigirdar, Adnan;
    Rosenberg, Steven A.;
    Parkhurst, Maria
  • Found In: Journal of immunotherapy: official journal of the Society for Biological Therapy. Volume 39:Issue 3 (2016, April)
  • Journal Title: Journal of immunotherapy: official journal of the Society for Biological Therapy
  • Subjects: Neoplasms--therapy--Periodicals; Electronic journals; Immunotherapy--Periodicals; WT1--immunotherapy--T-cell receptor; Dewey: 615.37
  • Rights: legaldeposit
  • Publication Details: Lippincott Williams & Wilkins
  • Abstract: Abstract :

    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.

    Abstract :

    Supplemental Digital Content is available in the text.


  • Identifier: System Number: LDEAvdc_100052996323.0x000001; Journal ISSN: 1524-9557; 10.1097/CJI.0000000000000116
  • Publication Date: 2016
  • Physical Description: Electronic
  • Shelfmark(s): ELD Digital store

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