• TLR4 is overexpressed on MM MSCs, and its activation promotes the crosstalk with MM cells in enhancing pro-tumoral factors

  • Specifically targeting TLR4 on MM MSCs strengthens conventional MM therapy and weakens MM development in vivo

Bone-marrow 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 pro-tumor activity of MSCs. Challenging primary MSCs with TLR4 agonists increased the expression of CD54 and interleukin 6, two 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 co-culture and in vivo with the Vk*MYC mouse model. Selective inhibition of TLR4 specifically reduced the MM MSC ability to support 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 bone-marrow microenvironment via TLR4 signaling could be an innovative approach to alter MM pathology development.

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