[en] Bone marrow (BM) mesenchymal stromal cells (MSCs) are abnormal in multiple myeloma (MM) and play a critical role by promoting growth, survival, and drug resistance of MM cells. We observed higher Toll-like receptor 4 (TLR4) gene expression in MM MSCs than in MSCs from healthy donors. At the clinical level, we highlighted that TLR4 expression in MM MSCs evolves in parallel with the disease stage. Thus, we reasoned that the TLR4 axis is pivotal in MM by increasing the protumor activity of MSCs. Challenging primary MSCs with TLR4 agonists increased the expression of CD54 and interleukin-6 (IL-6), 2 factors directly implicated in MM MSC-MM cell crosstalk. Then, we evaluated the therapeutic efficacy of a TLR4 antagonist combined or not with conventional treatment in vitro with MSC-MM cell coculture and in vivo with the Vk*MYC mouse model. Selective inhibition of TLR4 specifically reduced the MM MSC ability to support the growth of MM cells in an IL-6-dependent manner and delayed the development of MM in the Vk*MYC mouse model by altering the early disease phase in vivo. For the first time, we demonstrate that specific targeting of the pathological BM microenvironment via TLR4 signaling could be an innovative approach to alter MM pathology development.
Disciplines :
Immunology & infectious disease
Author, co-author :
Lemaitre, Léa ✱; Unit for Genomics of Myeloma, Institut Universitaire du Cancer Oncopole, Toulouse, France ; Centre de Recherche en Cancérologie de Toulouse INSERM U1037 team 13, Toulouse, France
Hamaïdia, Malik ✱; Université de Liège - ULiège > Département GxABT > Microbial technologies
Descamps, Jean-Gérard; Geroscience and Rejuvenation Research Center (RESTORE), Flames Team, INSERM 1301, UMR CNRS 5070, Univ. P. Sabatier, Toulouse, France ; EFS Occitanie, Toulouse, France
Do Souto Ferreira, Laura; Unit for Genomics of Myeloma, Institut Universitaire du Cancer Oncopole, Toulouse, France ; Centre de Recherche en Cancérologie de Toulouse INSERM U1037 team 13, Toulouse, France
Joubert, Marie-Véronique ; Unit for Genomics of Myeloma, Institut Universitaire du Cancer Oncopole, Toulouse, France ; Centre de Recherche en Cancérologie de Toulouse INSERM U1037 team 13, Toulouse, France
Gadelorge, Mélanie; Geroscience and Rejuvenation Research Center (RESTORE), Flames Team, INSERM 1301, UMR CNRS 5070, Univ. P. Sabatier, Toulouse, France ; EFS Occitanie, Toulouse, France
Avet-Loiseau, Hervé; Unit for Genomics of Myeloma, Institut Universitaire du Cancer Oncopole, Toulouse, France ; Centre de Recherche en Cancérologie de Toulouse INSERM U1037 team 13, Toulouse, France
Justo, Arthur ; Department of Orthopedic Surgery, Hôpital Pierre-Paul-Riquet, CHU de Toulouse, Toulouse, France ; AMIS Laboratory, Laboratoire Anthropologie Moléculaire et Imagerie de Synthèse, Université de Toulouse, UMR 5288 CNRS, UPS, Toulouse, France, and
Reina, Nicolas; Department of Orthopedic Surgery, Hôpital Pierre-Paul-Riquet, CHU de Toulouse, Toulouse, France ; AMIS Laboratory, Laboratoire Anthropologie Moléculaire et Imagerie de Synthèse, Université de Toulouse, UMR 5288 CNRS, UPS, Toulouse, France, and
Deschaseaux, Frederic; Geroscience and Rejuvenation Research Center (RESTORE), Flames Team, INSERM 1301, UMR CNRS 5070, Univ. P. Sabatier, Toulouse, France ; EFS Occitanie, Toulouse, France
Martinet, Ludovic; Unit for Genomics of Myeloma, Institut Universitaire du Cancer Oncopole, Toulouse, France ; Centre de Recherche en Cancérologie de Toulouse INSERM U1037 team 13, Toulouse, France
Bourin, Philippe ; Consultant and Independent Scientist, Cugnaux, France
Corre, Jill ; Unit for Genomics of Myeloma, Institut Universitaire du Cancer Oncopole, Toulouse, France ; Centre de Recherche en Cancérologie de Toulouse INSERM U1037 team 13, Toulouse, France
Espagnolle, Nicolas ; Geroscience and Rejuvenation Research Center (RESTORE), Flames Team, INSERM 1301, UMR CNRS 5070, Univ. P. Sabatier, Toulouse, France ; EFS Occitanie, Toulouse, France
This study was supported by internal funds of EFS Occitanie and by grants from Intergroupe Francophone du Myélome (IFM 2019-2021) (Geroscience and Rejuvenation Research Center [RESTORE], Flames Team, INSERM 1301, UMR CNRS 5070, Univ. P. Sabatier, EFS/ENVT); The Genomic and Immunology of Myeloma Laboratory at CRCT is supported by the Fondation ARC pour la Recherche sur le Cancer Program Grants (ARC PGA1-20160203788 and PGA1-20190208630). This work was supported by grants from the Institut National du Cancer
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