Cooperative function of CCR7 and lymphotoxin in the formation of a lymphoma-permissive niche within murine secondary lymphoid organs

Lymphoma cell survival and progression is putatively dependent on a specific microanatomical localisation within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable Emu-Myc transgenic mouse model, we show that the chemokine receptor CCR7 regulates Emu-Myc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T cell zone led to a significant survival advantage compared to CCR7-deficient lymphoma cells which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal crosstalk with gp38(+) fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cell-presented lymphotoxin which acted on lymphotoxin beta receptor-bearing stromal cells followed by alteration of stromal cellular composition. Crosstalk inhibition by lymphotoxin alpha deletion and by employing a lymphotoxin beta receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy.