Development of Cellular Immune Responses against PAX5, a Novel Target for Cancer Immunotherapy

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 highavidity T-cell receptor genes for use in adoptive immunotherapy.

Human γδ T Lymphocytes Are Licensed for Professional Antigen Presentation by Interaction with Opsonized Target Cells

“…In addition, we reasoned that opsonized Daudi cells could, in this model, serve as a source of TAA for processing and presentation on gd T MHC to other T cells in a rituximab-dependent manner. To test this, we investigated cross-presentation of PAX5 Ag, a nuclear transcription factor expressed in B lineage cancer cells including Daudi (22,23), by gd T MHC class I. We have previously described a CD8 CTL clone specific for the PAX5 peptide sequence TLPGYPPHV and restricted to HLA-A*0201 (22).…”

“…High-avidity CTL clones raised against HLA-A2-restricted epitopes, TLPGYPPHV derived from PAX5 and VLDGLDVLL derived from PRAME, have been previously described (21,22). To generate Ag-specific but Ag-inexperienced T cells, we transduced healthy donor PBMCs with a retrovirus expressing MART-1 TCR (containing a Vb12 chain) specific to an HLA-A*0201-restricted epitope, M26-35 (ELAGIGILTV).…”

Identification of hub genes and regulatory factors of glioblastoma multiforme subgroups by RNA-seq data analysis

“…It was recently reported that a splice variant of LCP2 resulted in severe immune dysregulation ( 32 ). The PAX5 encoded transcription factor is a PAX family member which plays important roles in B-cell development ( 33 ). Via the chromatin immunoprecipitation (ChIP) technique, PAX5 was found to regulate target genes by directly activating chromatin at the promoter or enhancer region, and PAX5 -activated targets are crucial regulators involved in B-cell signaling, migration and immune function ( 34 ).…”

High Proportions of CD4+ T Cells among Residual Bone Marrow T Cells in Childhood Acute Lymphoblastic Leukemia Are Associated with Favorable Early Responses

“…Moreover, the antigen specificity of individual memory CD8+ and CD4+ T cell clones among candidate antigens with known relevance in acute leukemias, e.g. WT-1 [43], PRAME [44], PAX5 [45], and their in vitro reactivity with autologous leukemic blasts will be determined. Together, these insights can contribute to the development of effective immunotherapeutic strategies.…”