CCR7 orchestrates the malignant progression of memory B cells in MYC-overexpressing lymphoma.

Follicular lymphoma (FL) is one of the most common types of indolent non-Hodgkin lymphoma that can undergo rapid progression, which is associated with poor patient outcomes. The homing of B cells into aberrant immunological niches within the germinal center (GC) is a prerequisite for disease development. The C-C chemokine receptor type 7 (CCR7), expressed by circulating B cells, mediates their homing and dissemination to draining lymph nodes (drLNs). Here, we identified activated B cells emerging from adjacent GCs in drLNs as the origin of circulating memory B cells in distant LNs. Transcriptional upregulation of Ccr7 in these memory B cells was found to guide their migration. To model lymphomagenesis, we generated a mouse model with B-cell-specific Myc overexpression, achieved by CRISPR/Cas9-mediated homologous recombination to insert a Myc expression cassette into the Hipp11 locus. Histological signs of aggressive lymphoma were evident in Ccr7 wild-type mice, whereas Ccr7 knockout mice exhibited pre-malignant atypia phenotypes. We in-depth revealed that Ccr7 knockout impeded the differentiation of pre-malignant Rnaseh2a+ memory B cells toward malignant Pax5+ GC B cells. Furthermore, Ccr7 deficiency attenuated the dependency of malignant memory or GC B cells on extensive follicular dendritic cell (FDC) networks and T-cell help. Conversely, IL-1β-induced FDC re-expansion preferentially fostered the proliferation of malignant GC B cells even in the context of Ccr7 knockout. Our findings reveal an unforeseen role for CCR7 in driving the malignant evolution of memory B cells by orchestrating their migratory dynamics and reprogramming the supportive GC niche.