title: Targeting B-cell malignancies through human B-cell receptor specific CD4+T cells.
abstract: The B-cell receptor (BCR) expressed by a clonal B cell tumor is a tumor specific antigen (idiotype). However, the T-cell epitopes within human BCRs which stimulate protective immunity still lack detailed characterization. In this study, we identified 17 BCR peptide-specific CD4+T-cell epitopes derived from BCR heavy and light chain variable region sequences. Detailed analysis revealed these CD4+T-cell epitopes stimulated normal donors' and patients' Th1 CD4+T cells to directly recognize the autologous tumors by secretion of IFNγ, indicating the epitopes are processed and presented by tumor cells. One BCR peptide-specific CD4+T cell line was also cytotoxic and lysed autologous tumor cells through the perforin pathway. Sequence analysis of the epitopes revealed that 10 were shared by multiple primary patients' tumors, and 16 had the capacity to bind to more than one HLA DRB1 allele. T cells stimulated by shared epitopes recognized primary tumors expressing the same sequences on multiple HLA DRB1 alleles. In conclusion, we identified 17 BCR-derived CD4+T-cell epitopes with promiscuous HLA DRB1 binding affinity that are shared by up to 36% of patients, suggesting a strategy to overcome the requirement for individual preparation of therapeutic agents targeting idiotype.
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Center Laboratory, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Jinsheng
authors.initials: J
authors.lastname: Weng
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Flavio Egidio
authors.initials: FE
authors.lastname: Baio
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Moriarty
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Torikai
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Sourindra N
authors.initials: SN
authors.lastname: Maiti
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Dongho
authors.initials: D
authors.lastname: Gwak
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Popescu
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Soung-Chul
authors.initials: SC
authors.lastname: Cha
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Laurence J N
authors.initials: LJ
authors.lastname: Cooper
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Sattva S
authors.initials: SS
authors.lastname: Neelapu
authors.affiliation: Department of Lymphoma and Myeloma, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
keywords: B-cell receptor; T cells; idiotype; immunotherapy