Increased Production of Immature Myeloid Cells in Cancer Patients: A Mechanism of Immunosuppression in Cancer

Abstract

Defective dendritic cell (DC) function caused by abnormal differentiation of these cells is an important mechanism of tumor escape from immune system control. Previously, we have demonstrated that the number and function of DC were dramatically reduced in cancer patients. This effect was closely associated with accumulation of immature cells (ImC) in peripheral blood. In this study, we investigated the nature and functional role of those ImC. Using flow cytometry, electron microscopy, colony formation assays, and cell differentiation in the presence of different cell growth factors, we have determined that the population of ImC is composed of a small percentage (<2%) of hemopoietic progenitor cells, with all other cells being represented by MHC class I-positive myeloid cells. About one-third of ImC were immature macrophages and DC, and the remaining cells were immature myeloid cells at earlier stages of differentiation. These cells were differentiated into mature DC in the presence of 1 μM all-trans-retinoic acid. Removal of ImC from DC fractions completely restored the ability of the DC to stimulate allogeneic T cells. In two different experimental systems ImC inhibited Ag-specific T cell responses. Thus, immature myeloid cells generated in large numbers in cancer patients are able to directly inhibit Ag-specific T cell responses. This may represent a new mechanism of immune suppression in cancer and may suggest a new approach to cancer treatment.

The inhibition of the T-cell immunoglobulin and mucin domain 3 (Tim3) pathway enhances the efficacy of tumor vaccine

“…First, Tim3 pathway inhibition may promote anti-tumor immunity by suppressing the generation of MDSCs. The frequency of MDSCs is increased in various tumors, the depletion of which leads to anti-tumor immunity and tumor regression [29][30][31][32]. In a Tim3 transgenic mouse model and a galectin-9 (Tim3 ligand) transgenic mouse model, an increase in MDSCs and inhibition of immune responses are observed [27].…”

An effective immunization and cancer treatment with activated dendritic cells transduced with full-length wild-type p53

“…33 Taking into consideration that tumor dramatically affects DC maturation, function and survival, 34,35 the induction of DC maturation in vitro may protect DCs from the negative influence of microenvironment in tumor tissue. This might also provide the most effective way of antigen presentation by DCs in vivo.…”

Nitric Oxide-Independent CTL Suppression during Tumor Progression: Association with Arginase-Producing (M2) Myeloid Cells

“…Knowledge about the mechanisms underlying tumor-induced immune defects is still largely fragmental. Indeed, various types of immune components are implicated in the down-regulation of antitumor responses, such as CD4 ϩ CD25 ϩ T regulatory cells (12), NKT cells (13), B cells (14), and myeloid suppressive cells (15)(16)(17)(18)(19)(20). In parallel, different malignancies cause diverse defects in T cells, ranging from alteration of signal transduction (20,21), induction of T cell tolerance/anergy (22), to triggering apoptosis in activated effector cells (23,24).…”