The IL32/BAFF axis supports prosurvival dialog in the lymphoma ecosystem and is disrupted by NIK inhibition

We demonstrated that the microenvironment-dependent secretion of IL32β was controlled by the CD40L/NFKB2 axis whereas its tumor specificity was the consequence of IL32 promoter hypomethylation in MCL. Through the secretion of IL32β, the tumor was able to corrupt its microenvironment through the polarization of monocytes into specific MCL-associated macrophages, which in turn favor tumor survival. We next highlighted that while IL32β-stimulated macrophages secreted several protumoral factors, they supported tumor survival through a soluble dialog, mostly driven by BAFF. Finally, we demonstrated the efficacy of selective NIK/alternative-NFkB inhibition to counteract both microenvironment-dependent induction of IL32β and BAFF-dependent survival of MCL cells. Peripheral Blood (PB) MCL cells were separated from other mononuclear cells using anti-human CD19-conjugated magnetic beads with purity >90%. For comparison with normal naive CD5+ B cells, cord blood B cells (NBC) were isolated and cultured using the same protocol. MCL and CD5+ B cells were cultured with growth factors (interleukin-10 [IL10]: 50 ng/mL, B-cell activating factor [BAFF]: 50 ng/mL, insulin-like growth factor-1 [IGF1]: 10 ng/mL, interleukin-6 [IL6]: 1 ng/mL) on adherent CD40L-expressing cells for 7 days.