Abstract
In multiple myeloma (MM), dendritic cells (DCs), and their precursors are prone to malignant cell-mediated regulation of function leading to low efficacy of DC vaccine. DCs taken directly from MM patient's body or derived from monocytes are fewer in numbers and are also dysfunctional. Here, we investigated the functionality of Hematopoietic stem cell-derived DCs (SC-DCs) from MM patients. Mature-MM-SC-DCs showed all essential functions like antigen uptake, allogenic T cells simulation and migration comparable to those derived from healthy donor (HD) samples. A comparison of Mo-DCs and SC-DCs obtained from the same MM patients' samples revealed that the expression of IL-6 was higher in the precursors of Mo-DCs leading to their impaired migration. In addition, expression of CCR7 which is responsible for DCs migration was found to be lower in MM-Mo-DCs. The chromatin permissiveness as observed by H3K4me3 histone modification at the Ccr7 promoter in MM-Mo-DCs was significantly lower than those in MM-SC-DCs. Levels of Zbtb46- a hall mark DC transcription factor mRNA was also found to be reduced in MM-Mo-DCs. Cytotoxic T cells generated from MM-SC-DCs from autologous naïve T cells exhibited reduced antitumor activity because the T cells were exhausted. Blocking of CTLA-4 on autologous T cells could partially restore T cell proliferation and activation. Thus, a combination of MM-SC-DC vaccine and anti-CTLA-4 antibody may serve as a better candidate for immunotherapy of MM. This study has implications in increasing the efficacy of cancer immunotherapy in MM.
Highlights
Multiple myeloma (MM) is a hematological malignancy with the second most common propensity with mortality rate of 5.2 to 8 [1]
Apheresis samples obtained from healthy donors (HD) or MM patients at remission were used for the generation of stem cell derived-dendritic cells (DCs) (SC-DCs)
Here we found that these functions were not compromised when DCs were generated from stem cells (MM-SC-DCs), with these showing migration (Figure 2F) and associated Ccr7 expression, equivalent to HD-SC-DCs (Figures 2G,H)
Summary
Multiple myeloma (MM) is a hematological malignancy with the second most common propensity with mortality rate of 5.2 to 8 [1]. Standard chemotherapy and radiation therapy, followed by autologous stem cell transplantation (AST), is the routine procedure administered to MM patients for treatment This standard treatment may help patients to achieve remissions but eventually majority of MM patients show relapse of the disease, with incurable progression associated with immune deregulation [4, 5]. Many studies, including ours, have suggested that DCs circulating in cancer patient’s body and monocytederived dendritic cells (Mo-DCs) are functionally impaired [13,14,15]. The precursors of these Mo-DCs secrete higher amounts of IL-6, leading to defective migration of Mo-DCs [16,17,18]. Apheresis samples obtained from healthy donors (HD) or MM patients at remission were used for the generation of stem cell derived-DCs (SC-DCs)
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