4.6 Article

Toll-like receptor 4 selective inhibition in medullar microenvironment alters multiple myeloma cell growth

Journal

BLOOD ADVANCES
Volume 6, Issue 2, Pages 672-678

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ELSEVIER
DOI: 10.1182/bloodadvances.2020003704

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Funding

  1. EFS Occitanie
  2. Intergroupe Francophone du Myelome (IFM 2019-2021) (Geroscience and Rejuvenation Research Center [RESTORE] , Flames Team, INSERM 1301, UMR CNRS 5070, Univ. P. Sabatier, EFS/ENVT)
  3. Fondation ARC pour la Recherche sur le Cancer Program Grants [ARC PGA1-20160203788, PGA1-20190208630]
  4. Institut National du Cancer [PLBIO R16100BB]
  5. Cancer Research Institute/Bristol-Myers Squibb CLIP Grant
  6. Fondation Toulouse Cancer Sante IUCT-O translational research program

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TLR4 gene is upregulated in abnormal BM mesenchymal stromal cells (MSCs) in multiple myeloma (MM), and its inhibition reduces MM cell growth and delays disease progression.
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 sup-port 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.

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