TY - JOUR AU - Decombis, Salomé AU - Papin, Antonin AU - Bellanger, Céline AU - Sortais, Clara AU - Dousset, Christelle AU - Le Bris, Yannick AU - Riveron, Thiphanie AU - Blandin, Stéphanie AU - Hulin, Philippe AU - Tessoulin, Benoit AU - Rouel, Mathieu AU - Le Gouill, Steven AU - Moreau-Aubry, Agnès AU - Pellat-Deceunynck, Catherine AU - Chiron, David PY - 2022/12/01 Y2 - 2024/03/28 TI - The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition JF - Haematologica JA - haematol VL - 107 IS - 12 SE - Articles DO - 10.3324/haematol.2021.279800 UR - https://haematologica.org/article/view/haematol.2021.279800 SP - 2905-2917 AB - Aggressive B-cell malignancies, such as mantle cell lymphoma (MCL), are microenvironment-dependent tumors and a better understanding of the dialogs occurring in lymphoma-protective ecosystems will provide new perspectives to increase treatment efficiency. To identify novel molecular regulations, we performed a transcriptomic analysis based on the comparison of circulating MCL cells (n=77) versus MCL lymph nodes (n=107) together with RNA sequencing of malignant (n=8) versus normal B-cell (n=6) samples. This integrated analysis led to the discovery of microenvironment-dependent and tumor-specific secretion of interleukin-32 beta (IL32β), whose expression was confirmed in situ within MCL lymph nodes by multiplex immunohistochemistry. Using ex vivo models of primary MCL cells (n=23), we demonstrated that, through the secretion of IL32β, the tumor was able to polarize monocytes into specific MCL-associated macrophages, which in turn favor tumor survival. We 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 microenvironment-dependent induction of IL32β and BAFF-dependent survival of MCL cells. These data uncovered the IL32β/BAFF axis as a previously undescribed pathway involved in lymphoma-associated macrophage polarization and tumor survival, which could be counteracted through selective NIK inhibition. ER -