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 C T-cell epitopes derived from BCR heavy and light chain variable region sequences. Detailed analysis revealed these CD4 C T-cell epitopes stimulated normal donors' and patients' Th1 CD4C T cells to directly recognize the autologous tumors by secretion of IFNg, indicating the epitopes are processed and presented by tumor cells. One BCR peptide-specific CD4 C 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 CD4C 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.

Personal tumor antigens in blood malignancies: genomics-directed identification and targeting

“…Idiotype-specific CD4 + T cells able to selectively lyse tumor cells have been isolated from peripheral blood of patients across different B cell malignancies (110). Khodadoust et al demonstrated that MHC II-restricted presentation of neoantigens arising from Ig rearrangement is common in mantle cell lymphoma.…”

Clinical and Antitumor Immune Responses in Relapsed/Refractory Follicular Lymphoma Patients after Intranodal Injections of IFNα-Dendritic Cells and Rituximab: a Phase I Clinical Trial

“…However, a strong induction of tumor-specific degranulating cytotoxic T cells, specific for either class-I-restricted CD8 or class-II-restricted CD4 idiotype epitopes, was detected in the peripheral blood of the 3 patients exhibiting a complete clinical response, showing a peak generally at 6-9 months after the beginning of the treatment, when objective clinical responses were observed. In this regard, it is worth mentioning that also tumor-specific CD4 þ T cells have recently been reconsidered as important effector cells in the immune control of B-cell lymphomas (34,35) because IGVH-derived neoantigens are most frequently presented by MHC-II (34) Although our preclinical studies (Fig. 1) and previous evidence by us (14)(15)(16)(17) and others, both in preclinical models (36) and patients (5), strongly support a critical role for DC, there is the remote hypothesis that rituximab can be also important for determining clinical and immune response.…”