1. The IL32/BAFF axis supports prosurvival dialogs in the lymphoma ecosystem and is disrupted by NIK inhibition
- Author
-
Decombis, Salomé, Papin, Antonin, Bellanger, Céline, Sortais, Clara, Dousset, Christelle, Le Bris, Yannick, Riveron, Thiphanie, Blandin, Stéphanie, Hulin, Philippe, Tessoulin, Benoit, Rouel, Mathieu, Le Gouill, Steven, Moreau-Aubry, Agnès, Pellat-Deceunynck, Catherine, Chiron, David, Centre de Recherche en Cancérologie et Immunologie Intégrée Nantes-Angers (CRCI2NA ), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), L’Héma-NexT [UNIV Nantes] (i-Site NexT), Université de Nantes (UN), Microenvironnement des niches tumorales (CNRS GDR 3697 Micronit ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Département d'Hématologie Clinique [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Hématologie Biologique [CHU Nantes], Plate-forme de 'transgénèse immunophénomique du rat' (P2R - INSERM UMS016/CNRS UMS3556/UN FED4203), Structure fédérative de recherche François Bonamy (SFR François Bonamy), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche en Santé de l'Université de Nantes (IRS-UN), and Chiron, David
- Subjects
immune system diseases ,hemic and lymphatic diseases ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Hematology ,[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] - Abstract
International audience; 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 (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 the 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-NFNB inhibition to counteract microenvironment-dependent induction of IL32β and BAFF-dependent survival of MCL cells. This data uncovered the IL32β/BAFF axis as a previously undescribed pathway involved in lymphoma-associated macrophages polarization and tumor survival, which could be counteracted through selective NIK inhibition.
- Published
- 2022