Immunotherapy in multiple myeloma

Optimizing immunotherapy in multiple myeloma: restoring the function of patient's monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in the progenitor cells

Siqing Wang, Sungyoul Hong, Jing Yang, Jianfei Qian, Xiang Zhang, Elizabeth Shpall, Larry W Kwak, and Qing Yi^*

University of Texas MD Anderson Cancer Center, Houston, TX, USA

Previous studies demonstrated that circulating dendritic cells (DCs) in myeloma patients were functionally abnormal. However, the phenotype and function of monocyte-derived DCs (MoDCs) from patients, which are commonly used for immunotherapy, were poorly defined. This study was undertaken to examine the quality of MoDCs from myeloma patients compared with cells from healthy donors. We found that patient-derived MoDCs are phenotypically and functionally defective. Compared with their normal counterpart, patient-derived, mature MoDCs expressed significantly lower levels of CD1a, CD40, CD80, and HLA-DR, and were poor at activating alloreactive T cells, presenting recall antigen and activating autologous antigen- and myeloma-specific T cells. These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6-specific antibody and more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield, but also produced MoDCs that were as functional as their normal counterpart. Thus, this study has delineated the mechanistic defects of MoDCs from myeloma patients, and identified ways for restoring the function of the cells to improve the efficacy of DC-based immunotherapy in this disease.