Spontaneous apoptosis of blood dendritic cells in patients with breast cancer

Pinzón-Charry, Alberto; Maxwell, Tammy; McGuckin, Michael A.; Schmidt, Chris; Furnival, Colin; López, José Alejandro

doi:10.1186/bcr1361

Cited by 50 publications

(49 citation statements)

References 36 publications

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“…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.…”

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

“…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. …”

mentioning

confidence: 85%

“…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].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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DC apoptosis has been observed in patients with cancer and sepsis, and defects in DC apoptosis have been implicated in the development of autoimmune diseases. However, the mechanisms of how DC apoptosis affects immune responses, are unclear. In this study, we showed that immature viable DC have the ability to uptake apoptotic DC as well as necrotic DC without it being recognized as an inflammatory event by immature viable DC. However, the specific uptake of apoptotic DC converted immature viable DC into tolerogenic DC, which were resistant to LPS-induced maturation. These tolerogenic DC secreted increased levels of TGF-b1, which induced differentiation of naïve T cells into Foxp3 1 Treg. Furthermore, induction of Treg differentiation only occurred upon uptake of apoptotic DC and not apoptotic splenocytes by viable DC, indicating that it is specifically the uptake of apoptotic DC that gives viable immature DC the potential to induce Foxp3 1 Treg. Taken together, these findings identify uptake of apoptotic DC by viable immature DC as an immunologically tolerogenic event.Key words: Apoptosis . Autoimmunity . DC . Tolerance Introduction DC are professional antigen-presenting cells, which are well positioned in peripheral tissues to capture foreign antigens. DC are phagocytic and can ingest apoptotic cells, and hence are affected by the death of other cells in close proximity [1][2][3]. Clearance of apoptotic cells results in their removal from tissues, and provides protection from release of pro-inflammatory contents. Necrotic cells impact the immune response by acting as ''danger signals'', whereas apoptotic cells are cleared without an immunological response [3,4]. Studies have identified necrotic cells acting as adjuvants, whereas apoptotic cells have been reported as immunogenic [5][6][7] or immunosuppressive [8,9]. DC apoptosis in itself is an important event for maintenance of tolerance. Defects in DC apoptosis have been linked to the development of autoimmunity with systemic autoimmune diseases modeled in transgenic mice harboring defects in DC apoptosis [10] but not in mice with apoptosis defects in T and B cells [11][12][13]. However, it is unclear how defects in DC apoptosis 1022can 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]. In this later stage, there is marked apoptosis of DC, with no effects on macrophage and neutrophil apoptosis. In addition, immunostimulants such as CpG DNA inhibit DC apoptosis [18], whereas the deficiency of pro-apoptotic Bim protein in DC results in autoimmunity [19].Immature DC have the ability to acquire protein complexes or soluble antigen using many different pathways such as macropinocytosis, endocytosis and even through ingestion of entire cells. Despite the importance of DC apoptosis in the immune response, studies ...

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Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…Few reports have assessed the effects of tumours on blood DC ex vivo (Gabrilovich et al, 1997;Hoffmann et al, 2002;Ratta et al, 2002;Della Bella et al, 2003) possibly due to their scarcity and heterogeneous nature. 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).…”

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confidence: 99%

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

Pinzón-Charry

Maxwell

et al. 2007

Br J Cancer

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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.

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Immunobiology of Dendritic Cells in Cancer

Shurin¹,

Chatta²

Tumor-Induced Immune Suppression

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Spontaneous apoptosis of blood dendritic cells in patients with breast cancer

Cited by 50 publications

References 36 publications

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

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

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

Immunobiology of Dendritic Cells in Cancer

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Spontaneous apoptosis of blood dendritic cells in patients with breast cancer

Cited by 50 publications

References 36 publications

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

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

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

Immunobiology of Dendritic Cells in Cancer

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

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