The Clonal Diversity of Peripheral B Cell Receptor Immune Repertoire Impaired by Residual Malignant B Cells Predicts Treatment Efficacy in B Cell Lymphoma Patients

SIMPLE SUMMARY: This study, for the first time, provided both in-vitro and clinical evidence that established a connection between the presence of residual malignant B cells and the clonal diversity of the resulting BCR repertoire. Lymphoma cells cultured with human germinal center B cells suppressed the normal increase of diversity. In a special setting of stem cell transplant, the retarded growth rate of a patient’s peripheral B cell diversity is of great prognostic potential for future relapse. ABSTRACT: Germinal center (GC) is the vital locus for the evolution of naïve B cells into memory B and plasma cells, but also a hotbed for the proliferation of malignant B cells. We hypothesized that malignant B cells may locally or globally impact GCs to produce peripheral B cell receptor immune repertoire (BCR IR) with reduced clonal diversity. In this study, we first validated our hypothesis in a novel human in-vitro GC (hiGC) model. The addition of the diffuse large B cell lymphoma (DLBCL) cells to the hiGC culture attenuated the rate of diversity growth. For clinical validation, we collected samples from 17 DLBCL patients at various points during high-dose therapy and autologous stem cell rescue. The elimination and reestablishment of the patients’ lymphatic pool allowed us to unambiguously monitor the impact of tumor cells on the replenishment of the peripheral BCR IR. Compared to the nine patients who did not relapse after treatment, relapsed patients tended to have a slower rate of recovery regarding the clonal diversity of their peripheral BCR IR. Our results suggest a mechanistic and clinical connection between residual tumor cells and abnormal peripheral BCR IR, which may corelate with treatment efficacy in B cell lymphomas.