Multiple myeloma (MM) patients are strongly vulnerable to infections, which remain a major cause of death. During infection, human immune cells sense the presence of invading pathogens through the Toll-like receptor family (TLR), which recognizes pathogen-associated molecular patterns (PAMP). We hypothesized that MM cells also could sense the presence of microorganisms, thus promoting myeloma disease progression. Here, we report that human myeloma cell lines (HMCL) and primary myeloma cells express a broad range of TLR, and are sensitive to the corresponding PAMP. Toll-like receptor 1, 7 and 9 are most frequently expressed by HMCL. The expression pattern of TLR does not correlate with the one of B cells, as TLR2 and 10 are lost while TLR3, 4 and 8 are acquired by some HMCL. Culture with TLR7-and TLR9-ligands saves HMCL from serum-deprivation or dexamethasone-induced apoptosis. Similarly, both ligands increase myeloma cell growth. These effects are mediated by an autocrine secretion of interleukin-6 (IL-6) since the neutralization of IL-6 blocks the growth and survival of HMCL. Thus, TLR expression and function are not restricted to the cells of the immune system and could be of advantage for cancer cells. In MM, recurrent infections could promote tumor growth and favor escape from standard therapies.

We evaluated the ability of 2 human mAbs directed against TRAILR1 (HGS-ETR1) and TRAILR2 (HGS-ETR2) to kill human myeloma cells. HGS-ETR1 and HGS-ETR2 mAbs killed 15 and 9 human myeloma cell lines (HMCLs; n ‫؍‬ 22), respectively. IL-6, the major survival and growth factor for these HMCLs, did not prevent their killing. Killing induced by either HGS-ETR1 or HGS-ETR2 was correlated with the cleavage of Mcl-1L, a major molecule for myeloma survival. Mcl-1L cleavage and anti-TRAILR HMCL killing were dependent on caspase activation. Kinetic studies showed that Mcl-1L cleavage occurred very early (less than 1 hour) and became drastic once caspase 3 was activated. Our data showed that both the extrinsic (caspase 8, Bid) and the intrinsic (caspase 9) pathways are activated by anti-TRAIL mAb. Finally, we showed that the HGS-ETR1 and, to a lesser extent, the HGS-ETR2 mAbs were able to induce the killing of primary myeloma cells. Of note, HGS-ETR1 mAb was able to induce the death of medullary and extramedullary myeloma cells collected from patients at relapse. Taken together, our data clearly encourage clinical trials of anti-TRAILR1 mAb in multiple myeloma, especially for patients whose disease is in relapse, at the time of drug resistance. (Blood. 2006;

The aim of this in vitro study was to evaluate if osteoclasts (OCs) and dendritic cells (DCs), both of monocyte origin, can support the survival of normal human plasma cells (PCs). PCs differentiate from plasmablasts (PBs) arising from activated B cells, essentially memory B cells. To study the survival of both PBs (CD20(low)CD38(high)CD138(neg)) and PCs (CD20(neg)CD38(bright)CD138(bright)), we generated pre-PBs (CD20(low)CD38(pos)CD138(neg)) from CD40-activated B cells (CD20(high)CD38(neg)CD138(neg)) and cultured them on DCs or OCs in the presence of added IL-6. By quantitative and qualitative study, we showed that DCs support the survival of PBs and early PCs, but not that of PCs. In contrast, OCs support the survival of PBs, early PCs and PCs. PCs surviving on OCs 12 days after pre-PB input display phenotypic features of bone marrow PCs, CD138(bright)CD38(bright)HLA-DR(low)CD45(dim). The ability for OCs to support the survival of PCs was fully dependent on cell-cell contact and not inhibited by BCMA-Fc suggesting that secreted BAFF and APRIL were not involved.