A Population of HLA-DR+ Immature Cells Accumulates in the Blood Dendritic Cell Compartment of Patients with Different Types of Cancer

Abstract

Dendritic cell (DC) defects are an important component of immunosuppression in cancer. Here, we assessed whether cancer could affect circulating DC populations and its correlation with tumor progression. The blood DC compartment was evaluated in 136 patients with breast cancer, prostate cancer, and malignant glioma. Phenotypic, quantitative, and functional analyses were performed at various stages of disease. Patients had significantly fewer circulating myeloid (CD11c+) and plasmacytoid (CD123+) DC, and a concurrent accumulation of CD11c(-)CD123(-) immature cells that expressed high levels of HLA-DR+ immature cells (DR(+)IC). Although DR(+)IC exhibited a limited expression of markers ascribed to mature hematopoietic lineages, expression of HLA-DR, CD40, and CD86 suggested a role as antigen-presenting cells. Nevertheless, DR(+)IC had reduced capacity to capture antigens and elicited poor proliferation and interferon-gamma secretion by T-lymphocytes. Importantly, increased numbers of DR(+)IC correlated with disease status. Patients with metastatic breast cancer showed a larger number of DR(+)IC in the circulation than patients with local/nodal disease. Similarly, in patients with fully resected glioma, the proportion of DR(+)IC in the blood increased when evaluation indicated tumor recurrence. Reduction of blood DC correlating with accumulation of a population of immature cells with poor immunologic function may be associated with increased immunodeficiency observed in cancer.

Immunosuppressive Strategies that are Mediated by Tumor Cells

“…This indicates that the lack of CD80/CD86 expression does not simply result from a lack of activation of these cells in the tumor microenvironment but might be caused by defects in cell differentiation (153). Consistent with these observations, an increased proportion of iDCs with reduced expression of co-stimulatory molecules was found in the peripheral blood of patients with breast, head and neck, lung, and esophageal cancers and similar data has been obtained in mouse tumor models (146)(147)(148)(149)(150)(151)(152)(153)(154). Immature DCs are unable to induce antitumour immune responses and can induce T-cell tolerance.…”

“…Patients had significantly fewer circulating myeloid DCs and pDC, and a concurrent accumulation of immature DCs. Immature DCs had reduced capacity to capture antigens and elicited poor proliferation and IFN-γ secretion by T-lymphocytes (149). Several clinical studies have provided clear evidence that surgical removal of tumors can increase the number of DCs in the peripheral blood of patients with cancer.…”

Parallel Loss of Myeloid and Plasmacytoid Dendritic Cells from Blood and Lymphoid Tissue in Simian AIDS

“…Despite the reduction of pDC and mature mDC in lymph nodes, we observed an increase in a population of Lin Ϫ HLA-DR mod CD11c Ϫ CD123 Ϫ cells within the Lin Ϫ HLA-DR ϩ fraction of lymph nodes from animals with AIDS that resemble monocytoid cells. Recently, an increased frequency of circulating blood DC lacking CD11c and CD123 expression that elicited poor T cell proliferation and IFN-␥ secretion was identified in cancer patients (55). In our study the Lin Ϫ HLA-DR mod cells did not acquire CD11c or CD123 expression after 24 h of culture, although it is conceivable that a longer period of culture would promote their differentiation.…”

Numerical and functional defects of blood dendritic cells in early- and late-stage breast cancer

“…In the case of breast cancer, circulating DC have been shown to be numerically reduced (Della Bella et al, 2003), exhibit increased rates of apoptosis (Pinzon-Charry et al, 2005c), and reduced capacity to stimulate T cells (Gabrilovich et al, 1997;Satthaporn et al, 2004). The DC compartment has also been shown to exhibit increased number of immature cells with impaired antigen-presenting capacity (Pinzon-Charry et al, 2005a, d). To date, however, only one -rather small -study has compared blood DC at different stages of disease (Gabrilovich et al, 1997) and no longitudinal studies have been reported.…”