Shaughnessy, John P.

Abstract We have previously shown (AAI2009) that dendritic cells (DC) contribute to the survival of long lived plasma cells in the bone marrow, which are important to maintain persistent antibody titres. What is not clear are the molecular interactions that are involved. Both normal and malignant plasma cells(like myeloma cells) express the T-cell co-stimulatory molecule CD28, and both interact with DCs in the bone marrow microenvironment. CD28 activation on MM triggers similar molecular partners downstream as observed in T-cells. Gene expression analysis of normal and malignant plasma cells shows that CD28 expression correlates with poor prognostic subgroups that are associated with specific genetic lesions. In our data, while activation of CD28 with antibodies or DC-CD80/CD86 (B7) protects myeloma cells against cell death, the ligation of B7 on DCs induces DC production of plasma cell survival factor IL-6, and immunosuppressive factor indoleamine 2,3-dioxygenase (IDO). Use of Lenalidomide (a common myeloma drug) to inhibit DC-B7 expression or anti-CD28(Fab)2 fragments to block CD28-B7 interactions reduced DC ability to protect MM cells. Experiments with αCD28(Fab)2 or inhibitors of notch pathway suggest a cross talk that regulates IL-6 production. IDO activity in DC-MM cocultures, suppressed T-cell proliferation in MLRs while an IDO inhibitor alleviated this. Our data suggests a role for CD28-B7 in plasma cell survival by modulating the bone marrow microenvironment.

Abstract Interactions between the malignant plasma cells of multiple myeloma and stromal cells within the bone marrow microenvironment are essential for myeloma cell survival, mirroring the same dependence of normal bone marrow-resident long-lived plasma cells on specific marrow niches. These interactions directly transduce prosurvival signals to the myeloma cells and also induce niche production of supportive soluble factors. However, despite their central importance, the specific molecular and cellular components involved remain poorly characterized. We now report that the prototypic T cell costimulatory receptor CD28 is overexpressed on myeloma cells during disease progression and in the poor-prognosis subgroups and plays a previously unrecognized role as a two-way molecular bridge to support myeloid stromal cells in the microenvironment. Engagement by CD28 to its ligand CD80/CD86 on stromal dendritic cell directly transduces a prosurvival signal to myeloma cell, protecting it against chemotherapy and growth factor withdrawal-induced death. Simultaneously, CD28-mediated ligation of CD80/CD86 induces the stromal dendritic cell to produce the prosurvival cytokine IL-6 (involving novel cross-talk with the Notch pathway) and the immunosuppressive enzyme IDO. These findings identify CD28 and CD80/CD86 as important molecular components of the interaction between myeloma cells and the bone marrow microenvironment, point to similar interaction for normal plasma cells, and suggest novel therapeutic strategies to target malignant and pathogenic (e.g., in allergy and autoimmunity) plasma cells.