LYMPHOID NEOPLASIA Dendritic cells accumulate in the bone marrow of myeloma patients where they protect tumor plasma cells from CD8 1 T-cell killing

Many researchers have speculated that the clinical progression from monoclonal gammop-athy of undetermined significance (MGUS) to multiple myeloma (MM) is driven by defects in dendritic cell (DC) function. However, evidence supporting this assumption is controversial, and no mechanism for the putative DC dysfunction has been demonstrated thus far. We studied DC subsets from the bone marrow of MM patients compared with those of MGUS patients and control subjects. We found that myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) accumulate in the bone marrow during the MGUS-to-MM progression. After engulfmentofapoptotictumorplasmacellsviaCD91,bonemarrowmDCsandpDCsmature and are able to activate tumor-specific CD8 1 T cells. However, by interacting directly with CD28onlive(nonapoptotic)tumorplasmacells,bonemarrowmDCsdownregulatetheexpressionofproteasomesubunitsinthesecells, thus enabling their evasion from human leukocyte antigen (HLA) class I–restricted CD8 1 T-cell killing. These results suggest that DCs playadual,butopposing,roleinMM:forone,DCsactivateCD8 1 Tcellsagainsttumorplasmacellsand,fortheother,DCsprotecttumor plasmacellsfromCD8 1 T-cellkilling.Thisinformationshouldbetakenintoaccountindesigningimmunotherapyapproachestoenhance immune surveillance in MGUS and to break down immune tolerance in MM. ( Blood . 2015;126(12):1443-1451) different ways of measuring DC activity have produced data 20-26 that cannot be compared and that do not often MGUS patients. Our paper provides a sharper picture of the distribution and func-tioning of DCs during the MGUS-to-MM progression. It shows that a considerable pool of mDCs and pDCs is “ stockpiled ” in BM in MGUS patients and even more so in MM patients. Marrow-resident mDCs and pDCs are fully capable of maturing and activating tumor-speci fi c CD8 1 T cells upon engulfment of apoptotic tumor plasma cells that present calreticulin on their surface. mDCs are also able to interact directly with live tumor plasma cells, downregulate the expression of proteasome subunits in these cells, and make them resistant to CD8 1 T-cell killing.