Compromised functionality of monocyte-derived dendritic cells in multiple myeloma patients may limit their use in cancer immunotherapy

Abstract

Dendritic cells (DCs) have the potential to elicit long-lasting anti-tumour immune responses. Most of the clinical trials of anti-cancer DC vaccines are based on monocyte-derived DCs (Mo-DCs). However, their outcomes have shown limited promise especially in multiple myeloma (MM) patients. Here, we investigated whether in vitro generated Mo-DCs from MM patients (MM-DCs) possess impaired functionality, thus contributing to the limited success of DC vaccines. We generated MM-DCs and compared them with DCs from healthy donors (HD-DCs). The yield of DCs in MM was 3.5 fold lower than in HD sets. However morphology, phenotype, antigen uptake and allo-T cell stimulation were comparable. Migration and secretion of IL12p70 and IFN-γ (in DC-T cell co-cultures) were significantly reduced in MM-DCs. Thus, MM-DCs were compromised in functionality. This impairment could be attributed to autocrine secretion of IL6 by MM-monocytes and activation of their P38 MAPK pathway. This indicates a need to look for alternative sources of DCs.

Standardization of sampling and sample preparation for analysis of human monocyte subsets in peripheral blood

“…MDSCs; see [369]). Quantitative and qualitative monocyte defects have been reported, including the reduced release of proinflammatory cytokines [378][379][380][381][382][383][384][385][386].…”

Dendritic Cells and Immunogenic Cancer Cell Death: A Combination for Improving Antitumor Immunity

“…One possible explanation is that mo-DCs that were obtained from cancer patients can express an altered phenotype, being characterized by a lower expression of co-stimulatory molecules and reduced ability to present antigens to T cells [182]. Furthermore, their maturational capacity can be affected, whereby mo-DCs may induce tolerogenic responses, regardless of the DC maturation stimulus [183][184][185]. On the other hand, it has been documented that patient-derived mo-DC functional bias is transient and tumor-dependent; in a few instances, ex vivo generated patient mo-DCs were indeed shown to recover a level of stimulatory activity that was comparable with healthy donor DCs after cancer surgery [186].…”

Caracterização genética e funcional de células dendríticas de indivíduos HIV+ estimuladas com flagelina

“…The CFSE Cell Division Tracker Kit (Biolegend) was used for flow cytometry analysis of in vitro CD4 + T cells proliferation assay according to manufacturers' protocol. Briefly, autologous lymphocytes were pre-treated with 0.1 µM CFSE before being added to MDDC cultures in the presence of the lymphocyte mitogen Concanavalin A (5 µg/mL; Sigma Aldrich, Merck) for 120 h (32). At the end of assay, cells were then labeled for anti-CD3 APC (MEM-57) and anti-CD4 PE (RPAT4) (BD Biosciences).…”

“…MDDC were treated with 5 µg/mL FLG for 24 h and phenotypic profile, TNF and IL-12 secretion as well as CD4 + T lymphocytes activation in co-culture experiments were assessed based on previously published protocols (31,32).…”

“…To test whether FLG-treated MDDC are able to induce a properly adaptive immunity response, a MDDC/lymphocytes coculture assay was performed using autologous cells as previously described (31,32). Lymphocytes alone were used as a negative control (Neg) (Figures 1D,E).…”