Either interleukin‐12 or interferon‐γ can correct the dendritic cell defect induced by transforming growth factor β₁ in patients with myeloma

Abstract

Summary The poor response to immunotherapy in patients with multiple myeloma (MM) indicates that a better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed. Recently we reported that high potency (CMRF44+) dendritic cells (DC) in the peripheral blood of patients with MM failed to significantly up‐regulate the expression of the B7 co‐stimulatory molecules, CD80 and CD86, in response to an appropriate signal from soluble trimeric human CD40 ligand. This defect was caused by transforming growth factor β1 (TGFβ1) and interleukin (IL)‐10, produced by malignant plasma cells, and the defect was neutralized in vitro with anti‐TGFβ1. As this defect could impact on immunotherapeutic strategies and may be a major cause of the failure of recent trials, it was important to identify a more clinically useful agent that could correct the defect in vivo. In this study of 59 MM patients, the relative and absolute numbers of blood DC were only significantly decreased in patients with stage III disease and CD80 up‐regulation was reduced in both stage I and stage III. It was demonstrated that both IL‐12 and interferon‐γ neutralized the failure to stimulate CD80 up‐regulation by huCD40LT in vitro. IL‐12 did not cause a change in the distribution of DC subsets that were predominantly myeloid (CD11c+ and CDw123−) suggesting that there would be a predominantly T‐helper cell type response. The addition of IL‐12 or interferon‐γ to future immunotherapy trials involving these patients should be considered.

Laboratory Characterizations on 2007 Cases of Monoclonal Gammopathies in East China

“…A better understanding of any defects in the immune response in these patients is required before effective therapeutic strategies can be developed (24). Several studies supported that myeloma tumor cells in MM, the most common disease type in monoclonal gammopathies, evaded the immune system and could induce immunosuppression by producing immunoregulatory factors such as TGFβ1 (25).…”

Tumour-released exosomes and their implications in cancer immunity

“…[20][21][22][23] However, it is worth mentioning that soluble factors are likely to act mostly locally or in the immediate vicinity of the releasing site, and they could hardly be deemed to be the only cause of the systemic and multiple effects than can be observed in the peripheral blood or bone marrow of cancer patients. In this view, more efficient pathways for the delivery of immune suppressive/deviating signals by tumour cells to the immune system should exist to explain the systemic dysfunctions observed in cancer patients.…”

Analysis of the immune system of multiple myeloma patients achieving long-term disease control by multidimensional flow cytometry

“…12,13 Moreover, dendritic cells (DC) have also been reported to be altered in MM, with reductions in circulating myeloid DC (m-DC) and plasmacytoid DC (p-DC), lower expression of co-stimulatory molecules and impaired induction of allogeneic T-cell responses. [14][15][16] Since these immune defects are invariably present in active MM, we hypothesized that the immune system may play a critical role in LTDC-MM patients. To explore this possibility, in the present study we compared the distribution of many different subsets of T-B -and NK-lymphocytes and DC in both the BM and PB of MM patients who achieved long term disease control (LTDC-MM) versus the distributions in patients with newly diagnosed MGUS and symptomatic MM, as well as in healthy adults of similar age.…”