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

Abstract

The generation of antitumour immunity depends on the nature of dendritic cell (DC) -tumour interactions. These have been studied mostly by using in vitro-derived DC which may not reflect the natural biology of DC in vivo. In breast cancer, only one report has compared blood DC at different stages and no longitudinal evaluation has been performed. Here we conducted three cross-sectional and one one-year longitudinal assessments of blood DC in patients with early (stage I/II, n ¼ 137) and advanced (stage IV, n ¼ 36) disease compared to healthy controls (n ¼ 66). Patients with advanced disease exhibit markedly reduced blood DC counts at diagnosis. Patients with early disease show minimally reduced counts at diagnosis but a prolonged period (1 year) of marked DC suppression after tumour resection. While differing in frequency, DC from both patients with early and advanced disease exhibit reduced expression of CD86 and HLA-DR and decreased immunostimulatory capacities. Finally, by comparing a range of clinically available maturation stimuli, we demonstrate that conditioning with soluble CD40L induces the highest level of maturation and improved T-cell priming. We conclude that although circulating DC are compromised by loco-regional and systemic breast cancer, they respond vigorously to ex vivo conditioning, thus enhancing their immunostimulatory capacity and potential for immunotherapy.

Uptake of apoptotic DC converts immature DC into tolerogenic DC that induce differentiation of Foxp3+ Treg

“…High levels of spontaneous DC apoptosis have also been observed in breast cancer patients, with its significance being unclear [15,16]. Our study indicates that DC apoptosis in cancer patients may play a role in suppressing immune responses against the tumor by inducing immunosuppression and tolerance.…”

“…Our study indicates that DC apoptosis in cancer patients may play a role in suppressing immune responses against the tumor by inducing immunosuppression and tolerance. Therefore, prevention of DC apoptosis may enhance the therapeutic effects of chemotherapy in tumor eradication [15,16].…”

“…Our study indicates that DC apoptosis in cancer patients may play a role in suppressing immune responses against the tumor by inducing immunosuppression and tolerance. Therefore, prevention of DC apoptosis may enhance the therapeutic effects of chemotherapy in tumor eradication [15,16].Our findings may also represent a therapeutic approach in the prevention of unwanted immune responses in autoimmune diseases and transplantation along with inhibition of DC apoptosis to assist in tumor eradication. …”

“…However, it is unclear how defects in DC apoptosis can trigger autoimmune responses. Furthermore, spontaneous DC apoptosis has been reported in sepsis as well as breast cancer patients with its significance being unclear [14][15][16]. Most patient deaths associated with sepsis occur at later time points and are associated with prolonged immunosuppression [17].…”

Histamine Promotes the Development of Monocyte-Derived Dendritic Cells and Reduces Tumor Growth by Targeting the Myeloid NADPH Oxidase

“…The accumulating progenitor cells are suppressive to several aspects of T cell-mediated immunity and do not efficiently develop into Agpresenting dendritic cells (DCs), thus impeding presentation of tumor-derived Ags to T cells (1)(2)(3). Several studies demonstrated that accumulation of immature myeloid cells and the absence of mature DCs result in accelerated tumor growth and poor outcome in human and murine cancers (1,(3)(4)(5)(6). Therefore, understanding the regulation of myeloid cell differentiation, in particular with regard to the development of DCs, may provide novel therapeutic targets (2).…”