Abstract
PAX5 is a member of the PAX family of developmental transcription factors with an important role in B-cell development. Its expression in normal adult tissue is limited to the hemopoietic system, but it is aberrantly expressed in a number of solid cancers and leukemias where it functions as an oncogene. We therefore hypothesized that anti-PAX5 immune responses could be used to target a number of malignancies without significant toxicity. We screened PAX5 peptides for the ability to bind HLA-A2 and identified a novel sequence, TLPGYPPHV (referred to as TLP). CTL lines against TLP were generated from peripheral blood of five normal HLA-A2-positive blood donors and showed specific HLA-A2-restricted killing against PAX5-expressing target cells. We generated high-avidity CTL clones from these lines capable of killing cells pulsed with <1 nmol/L of TLP and killing a range of PAX5-expressing malignant cell lines. I.v. injection of an anti-PAX5 CTL clone into immunodeficient mice bearing s.c. human tumors resulted in specific growth inhibition of PAX5-expressing tumors. This knowledge can be used for the therapeutic generation of CTL lines or the cloning of high-avidity T-cell receptor genes for use in adoptive immunotherapy.
Highlights
The ultimate goal of cancer immunotherapy is the development of specific, sustained, and potent antitumor immune responses with minimal toxicity
PAX5 is identified as a potential target for cancer immunotherapy by virtue of its limited normal developmental expression but high-level expression in a range of adult and pediatric cancers
Previous workers have shown that PAX5 is critical for B-cell specification and for maintenance of B-cell phenotype, such that loss of PAX5 is tumorigenic for B-cell leukemia [15, 30]
Summary
The ultimate goal of cancer immunotherapy is the development of specific, sustained, and potent antitumor immune responses with minimal toxicity. Impressive clinical and immunologic responses have followed adoptive transfer of expanded lymphocytes derived from autologous melanoma tumors [1, 2]. The study of melanoma tumor infiltrating lymphocytes has been instrumental in the identification of immunogenic tumor antigens and the subsequent development of cancer vaccine therapies. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Ideal putative tumor antigens have the following three characteristics: high expression in the tumor, low expression in normal tissues, and a critical role in oncogenesis. This ‘‘candidate antigen’’ approach has been used successfully for a number of potential immunotherapy targets lacking evidence of natural immunogenicity. None of the above-mentioned antigens have all three of the hallmarks
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