Dendritic cells are dysfunctional in patients with operable breast cancer

Satthaporn, Sukchai; Robins, Adrian; Vassanasiri, Wichai; ElSheemy, Mohammed S.; Jibril, Jibril A; Clark, David W.; Valerio, D; Eremin, O.

doi:10.1007/s00262-003-0485-5

Cited by 115 publications

(87 citation statements)

References 42 publications

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“…In breast cancer, blood DC counts have been found decreased (Della Bella et al, 2003) although extensive comparative analyses of early vs advanced disease have not yet been described. Our results extend published data (Gabrilovich et al, 1997;Della Bella et al, 2003;Satthaporn et al, 2004) and demonstrate that diminished numbers of DC correlate with more extended disease. Although patients with early disease showed only discrete (not significant) reductions in counts at diagnosis, suppression of DC was clearly evident upon follow-up.…”

Section: Discussionsupporting

confidence: 92%

“…In fact, significant apoptosis of blood DC in patients with breast cancer has been reported to be associated with tumour products (Pinzon-Charry et al, 2005c). This phenomenon would certainly impose chronic stress on the immune system of these patients and result in progressive paucity of DC in the circulation (Lissoni et al, 1999;Della Bella et al, 2003), failure to replenish tumour-infiltrating DC and impaired migration of DC to lymphoid organs (Satthaporn et al, 2004) for the initiation of T-cell responses.…”

Section: Discussionmentioning

confidence: 99%

“…The important implication for these patients is that although DC may 'seem' normal, their reduced functionality (Gabrilovich et al, 1997;Della Bella et al, 2003;Satthaporn et al, 2004) could indeed favour tumour progression by failing to induce adequate antitumour immunity. From an immunotherapy standpoint, such in vivo deficiencies should be overcome (Pinzon-Charry et al, 2006a).…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…However, tumor production of immunosuppressive factors (cytokines, arachidonic acid metabolites, glycosphingolipids, polyamines) with detrimental effects on DC maturation and function can significantly prevent antitumor immune responses (22). It was reported (23,24) that tumor-infiltrating DCs are neither mature nor activated and blood dendritic cells in breast cancer patients express low levels of co-stimulatory molecules and IL-12 along with an impaired capacity to stimulate T-cells. The in vivo longevity of DCs was recognized as a necessary factor for priming and maintaining effective antitumor immune responses and one way to achieve this is to prevent the apoptotic pathways in the DCs (25).…”

Section: Discussionmentioning

confidence: 99%

In vitro antitumor cytotoxic T lymphocyte response induced by dendritic cells transduced with ΔNp73α recombinant adenovirus

Hu¹,

He²,

Srivenugopal³

et al. 2007

Oncol Rep

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Abstract. ΔNp73α, the N-terminal truncated form of p73α is a candidate tumor antigen because of its selective expression in many human cancers and lack of expression in normal tissues. Therefore, we investigated the effects of dendritic cells infected with adenoviral ΔNp73α (DNp73α) on breaking immune tolerance and induction of immunity against DNp73α-expressing (A549 lung cancer, K-562 leukemia) and nonexpressing (MCF-7 breast cancer) cell lines. Immature dendritic cells generated in the presence of interleukin-4 and granulocyte/macrophage colony-stimulating factor from a human umbilical cord blood were transduced with a recombinant adenoviral (Ad) vector encoding full-length human DNp73α cDNA (Ad-DNp73α) or a control vector Ad-EGFP, using the centrifugal force method. Induction of DNp73α-specific CTL response was evaluated by a cytotoxic assay against the three human tumor cell lines with different DNp73α expression levels. The viability and activation status of transduced dendritic cells were assessed by flow cytometry. The dendrocyte/Ad-DNp73α-activated cytotoxic T lymphocytes showed significantly higher cytotoxicity against the cell lines A549/DNp73α, K-562 that expressed DNp73α than the DNp73α-null MCF-7 cells. The DCs/Ad-DNp73α showed higher survival rates than the DCs/Ad-EGFP or untransduced DCs, presumably due to the inhibition of cell death. These findings, with potential applications for immunotherapy, demonstrate that dendrocytes transduced with Ad-DNp73α can induce specific and sustained T cell responses against tumors expressing this variant p53-related gene.

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CRISPR Technology for Breast Cancer: Diagnostics, Modeling, and Therapy

Mintz

Gao

et al. 2018

Adv. Biosys.

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Molecularly, breast cancer represents a highly heterogenous family of neoplastic disorders, with substantial interpatient variations regarding genetic mutations, cell composition, transcriptional profiles, and treatment response. Consequently, there is an increasing demand for alternative diagnostic approaches aimed at the molecular annotation of the disease on a patient‐by‐patient basis and the design of more personalized treatments. The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated (Cas) technology enables the development of such novel approaches. For instance, in diagnostics, the use of the RNA‐specific C2c2 system allows ultrasensitive nucleic acid detection and could be used to characterize the mutational repertoire and transcriptional breast cancer signatures. In disease modeling, CRISPR/Cas9 technology can be applied to selectively engineer oncogenes and tumor‐suppressor genes involved in disease pathogenesis. In treatment, CRISPR/Cas9 can be used to develop gene‐therapy, while its catalytically‐dead variant (dCas9) can be applied to reprogram the epigenetic landscape of malignant cells. As immunotherapy becomes increasingly prominent in cancer treatment, CRISPR/Cas9 can engineer the immune cells to redirect them against cancer cells and potentiate antitumor immune responses. In this review, CRISPR strategies for the advancement of breast cancer diagnostics, modeling, and treatment are highlighted, culminating in a perspective on developing a precision medicine‐based approach against breast cancer.

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Dendritic cells are dysfunctional in patients with operable breast cancer

Abstract: These data suggest a defective DC function in patients with operable breast cancer. Switched-off DCs in patients with early breast cancer and decreased IL-12 production may be important factors for progressive tumour growth.

Cited by 115 publications

References 42 publications

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

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

In vitro antitumor cytotoxic T lymphocyte response induced by dendritic cells transduced with ΔNp73α recombinant adenovirus

CRISPR Technology for Breast Cancer: Diagnostics, Modeling, and Therapy

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