Dendritic cells from CML patients have altered actin organization, reduced antigen processing, and impaired migration

Dong, Rong; Cwynarski, Kate; Entwistle, Alan; Marelli‐Berg, Federica M.; Dazzi, Francesco; Simpson, Elizabeth; Goldman, John M.; Melo, Junia V.; Lechler, Robert I.; Bellantuono, Ilaria; Ridley, Anne J.; Lombardi, Giovanna

doi:10.1182/blood-2002-06-1841

Cited by 89 publications

(88 citation statements)

References 37 publications

(56 reference statements)

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“…in chronic myeloid leukaemia DCs may be related to the underlying cytoskeletal changes induced by the expression of the BCR-ABL fusion gene (Dong et al, 2003). At present, we cannot exclude the fact that cytoskeletal alterations may similarly contribute to impaired function of DCs in breast cancer patients.…”

Section: Discussionmentioning

confidence: 87%

“…Functional impairment of DCs have also been described in haematologic diseases, in particular in chronic and acute myeloid leukaemia, in which defects in antigen processing (Dong et al, 2003) and in allostimulatory activity (Mohty et al, 2001) have been related to the expression by DCs of the same cytogenetic abnormalities expressed by freshly isolated leukaemic cells. It has been suggested that the defects in antigen processing observed Figure 8 Analysis of T-cell division induced at different days by allogenic unconditioned (white squares) or spermine-conditioned (black squares) DCs.…”

Section: Discussionmentioning

confidence: 99%

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Altered maturation of peripheral blood dendritic cells in patients with breast cancer

et al. 2003

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Tumours have at least two mechanisms that can alter dendritic cell (DC) maturation and function. The first affects the ability of haematopoietic progenitors to differentiate into functional DCs; the second affects their differentiation from CD14 þ monocytes, promoting an early but dysfunctional maturation. The aim of this study was to evaluate the in vivo relevance of these pathways in breast cancer patients. For this purpose, 53 patients with invasive breast cancer were compared to 68 healthy controls. To avoid isolation or culture procedures for enrichment of DCs, analyses were directly performed by flow cytometry on whole-blood samples. The expression of surface antigens and intracellular accumulation of regulatory cytokines upon LPS stimulation were evaluated. The number of DCs, and in particular of the myeloid subpopulation, was markedly reduced in cancer patients (Po0.001). Patient DCs were characterized by a more mature phenotype compared with controls (P ¼ 0.016), and had impaired production of IL-12 (Po0.001). These alterations were reverted by surgical resection of the tumour. To investigate the possible role of some tumourrelated immunoactive soluble factors, we measured the plasmatic levels of vascular endothelial growth factor, IL-10 and spermine. A significant inverse correlation between spermine concentration and the percentage of DCs expressing IL-12 was found. Evidence was also obtained that in vitro exposure of monocyte-derived DCs to spermine promoted their activation and maturation, and impaired their function. Taken together, our results suggest that both the above-described mechanisms could concomitantly act in breast cancer to affect DC differentiation, and that spermine could be a mediator of dysfunctional maturation of DCs.

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Altered maturation of peripheral blood dendritic cells in patients with breast cancer

et al. 2003

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“…WAS-patient macrophages (Linder et al, 1999) and dendritic cells from CML patients (Dong et al, 2003) both display pronounced defects in podosome formation and chemotaxis.…”

Section: Diseasementioning

confidence: 99%

Podosomes at a glance

Linder

Kopp

2005

Journal of Cell Science

190

199

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“…The fact that bone marrow transplantation with allogeneic cells causes graft versus leukemia provides strong evidence that the host immune system is capable of controlling leukemia (Butturini and Gale, 1995;Platzbecker et al, 2004). These and other findings (O'Keefe et al, 2004) suggest that impairment of leukemia-specific immune responses occurs in leukemia patients, and this abnormality may be due to oncoproteins, such as BcrAbl in chronic myeloid leukemia, which cause immune dysfunction in hematopoietic cells (Dong et al, 2003).…”

Section: Introductionmentioning

confidence: 94%

Vaccination with leukemia cells expressing cell-surface-associated GM-CSF blocks leukemia induction in immunocompetent mice

et al. 2006

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The fundamental basis for immunotherapy of leukemia is that leukemic cells express specific antigens that are not expressed by normal hematopoietic cells. However, the host immune system appears to be tolerant to leukemia cells. To overcome this tolerance, we vaccinated immunocompetent mice with murine leukemia cells (WEHI-3B and BCR-ABL þ 32D cells) transduced with a specifically constructed transmembrane form of granulocytemacrophage colony-stimulating factor (tmGM-CSF). The transduced cells expressed tmGM-CSF on the cellsurface. To determine whether tmGM-CSF-expressing WEHI-3B leukemia cells would prevent leukemia formation as a vaccine, immunocompetent mice (BALB/c and C3H/HEJ) were immunized with lethally irradiated murine leukemia cells expressing cell-surface tmGM-CSF before challenging mice with murine leukemia cells. Two immunocompetent mouse models were investigated, either WEHI-3B cells in BALB/c mice or BCR-ABL þ 32D cells in C3H/HEJ mouse. The results showed that 100% of WEHI-3B/tmGM-CSF-vaccinated BALB/c mice and about 65% of 32D þ BCR-ABL/tmGM-CSFvaccinated C3H/HEJ mice were protected from leukemia after leukemia cell challenge, whereas all non-vaccinated mice succumbed to leukemia. Spleen and marrow cell suspensions from vaccinated mice challenged with WEHI-3B cells lacked detectable GFP þ WEHI-3B cells at 82 days post-challenge. A significant delay of death was observed in C3H/HEJ mice challenged with the very aggressive DA-1 cell line expressing BCR-ABL. Vaccination of mice with WEHI-3B/CD40L cells protected 80% of the mice from the WEHI-3B challenge. Notably, 60% of the WEHI-3B/BALB/c mice were also protected from leukemia when WEHI-3B/tmGM-CSF vaccination was carried out after the leukemia challenge. In order to determine whether cellular immunity is involved in this vaccine-mediated protection, either CD4 þ or CD8 þ T cells were depleted from mice after the WEHI-3B/tmGM-CSF vaccination. The results indicate that CD8 þ T-cells mediated the protective immune response provided by the irradiated tmGM-CSF-expressing WEHI-3B cells.In addition, vaccination of nude mice did not provide protection from WEHI-3B leukemia induction. Importantly, 80% of non-vaccinated mice were also protected from a WEHI-3B cell challenge after receiving spleen cells from vaccinated mice 1 day before challenge with leukemia cells. These results indicate that overexpression of tmGM-CSF on the leukemia cell-surface can enhance the recognition of leukemic cells by CD8 þ T cells, and can either prevent or significantly delay leukemia induction. These findings suggest that injection of irradiated leukemia cells expressing cell-surface-bound GM-CSF has the potential as an immunological approach to treat leukemia.

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Dendritic cells from CML patients have altered actin organization, reduced antigen processing, and impaired migration

Cited by 89 publications

References 37 publications

Altered maturation of peripheral blood dendritic cells in patients with breast cancer

Altered maturation of peripheral blood dendritic cells in patients with breast cancer

Podosomes at a glance

Vaccination with leukemia cells expressing cell-surface-associated GM-CSF blocks leukemia induction in immunocompetent mice

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