Development of cellular immune responses against PAX5, a novel target for cancer immunotherapy.
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.
Yan
Mengyong
M
Units of Molecular Haematology and Cancer Biology, Institute of Child Health, University College London, London, United Kingdom.
Himoudi
Nourredine
N
Pule
Martin
M
Sebire
Neil
N
Poon
Edmund
E
Blair
Allison
A
Williams
Owen
O
Anderson
John
J
D000818:Animals; D049109:Cell Proliferation; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003182:Complement C5 / Q000235:genetics; D016654:Genes, RAG-1 / Q000502:physiology; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology; D016219:Immunotherapy, Adoptive / Q000379:methods; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D020014:K562 Cells; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051757:PAX5 Transcription Factor / Q000037:antagonists & inhibitors* / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D003182:Complement C5; D053631:Interleukin Receptor Common gamma Subunit; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human