Pathogen-Associated Molecular Patterns Are Growth and Survival Factors for Human Myeloma Cells through Toll-Like Receptors.

Abstract

Multiple Myeloma (MM) patients are strongly sensitive to bacterial, fungal and viral infections. Furthermore, MM is often newly diagnosed in the context of such infections. Given those recurrent infections remain a major cause of death of MM patients; we surmised that MM plasma-cells could be activated by microorganisms, therefore contributing to the initiation and progression of the disease. Microorganisms share highly conserved structures called pathogen-associated molecular patterns. They are recognized by a family of receptors that act as sensor for the innate immune system and are called the Toll-like receptor family (TLRs). We first measured the expression of the 10 known human TLRs on 16 human MM plasma-cells lines (HMCLs) and freshly purified Plasma-cells from 13 patients. The expression pattern is heterogeneous among HMCLs and does not correlate with the one of B cells. Indeed TLR-3, 4, and 8 are aberrantly expressed. On the contrary, the expression of TLR-2 and 10 is lost on most of the HMCLs. TLR-1, 7 and 9 are the most frequently expressed (15+/16, 12+/16 and 11+/16 respectively). Primary MM plasma-cells also express TLR-7 (9+/13) and TLR-9 (8+/13). Accordingly to this expression profile, culture with TLR-7 ligand (loxoribine) or TLR-9 ligand (hypomethylated DNA from bacteria) increased 1,7 to 6 times (mean 3 ± 1,4 n= 8) the proliferation of IL-6-dependent and independent HMCLs. Furthermore, we observed a resistance to serum-deprivation as well as to dexamethasone-induced apoptosis. Those effects were IL-6-mediated in IL-6-dependent HMCLs since a blocking antibody to IL-6 neutralized the growth and survival induced by TLR triggering. In conclusion, human MM Plasma-cells express a broad range of TLRs and the triggering of TLR-7 and 9 induces tumor cell growth and prevent chemotherapy-induced apoptosis. These effects are mediated by the induction of an autocrine loop of growth factors as IL-6, and others currently under identification in the case of IL-6 independent HMCLs. Thus, MM plasma-cells take advantage of infections to expand and escape to usual therapies.