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

Abstract

Key Points• Dendritic cells accumulate in the bone marrow of multiple myeloma patients.• Bone marrow dendritic cells play a dual, but opposing, role in multiple myeloma.Many researchers have speculated that the clinical progression from monoclonal gammopathy 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 engulfment of apoptotic tumor plasma cells via CD91, bone marrow mDCs and pDCs mature and are able to activate tumor-specific CD8 1 T cells. However, by interacting directly with CD28 on live (nonapoptotic) tumor plasma cells, bone marrow mDCs downregulate the expression of proteasome subunits in these cells, thus enabling their evasion from human leukocyte antigen (HLA) class I-restricted CD8 1 T-cell killing. These results suggest that DCs play a dual, but opposing, role in MM: for one, DCs activate CD8 1 T cells against tumor plasma cells and, for the other, DCs protect tumor plasma cells from CD8 1 T-cell killing. This information should be taken into account in designing immunotherapy approaches to enhance immune surveillance in MGUS and to break down immune tolerance in

Bone marrow endothelial cells sustain a tumor-specific CD8+ T cell subset with suppressive function in myeloma patients

“…It has been recently recognized that both patients with MGUS and those with MM have, in the bone marrow, tumor-specific CD8 + T cells that are, however, unable to limit the expansion of the malignant plasma cells. [2][3][4][5] Tumor-specific CD8 + T cells flooding into the bone marrow initially encounter endothelial cells (EC) that line the bone marrow microsinusoids. Trafficking of CD8 + T cells between blood and bone marrow is facilitated by the discontinuous basement membrane and the EC fenestrations of sinusoids.…”

Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication

“…[10][11][12] They are recruited by MM cells to create a localized immunosuppressive niche for MM survival. OCs are terminally differentiated cells of the monocyte/macrophage lineage with similar immune receptors in the innate immune system.…”

Daratumumab prevents programmed death ligand‐1 expression on antigen‐presenting cells in de novo multiple myeloma

“…Indeed, it has been shown that pDC confer a growth and survival advantage to MM cells . More precisely, the pDC antitumor function, through the decrease of cytotoxic CD8 T‐cell activation, is abolished by MM cells . Therefore, the decreased number of pDC associated with the use of Dara suggests an additional mechanism of action of Dara through pDC depletion.…”

“…19 More precisely, the pDC antitumor function, through the decrease of cytotoxic CD8 T-cell activation, is abolished by MM cells. 20 Therefore, the decreased number of pDC associated with the use of Dara suggests an additional mechanism of action of Dara through pDC depletion. Recently, Chen et al 12 demonstrated that CD38 upregulation in tumors induces resistance to PD-1/PD-L1 blocking antibodies and coinhibition of CD38 and PD-L1 improves antitumor immune response.…”