Leukemic cell products down-regulate human dendritic cell differentiation

Motta, Juliana María; Nascimento, Christine Rabello; Rumjanek, Vivian M.

doi:10.1007/s00262-010-0890-5

Cited by 12 publications

(27 citation statements)

References 31 publications

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“…It was recently shown that TEM-8 is upregulated in tumor-associated endothelial cells after exposure to interleukin-1β (IL-1β) [21]; interestingly, IL-1β, together with tumor necrosis factor-α (TNF-α) and other cytokines produced by tumor cells (melanoma included) [22], can negatively affect the differentiation of monocyte-derived DC in vitro [23]. As IL-1β and TNF-α are components of the cytokine maturation cocktail currently used to prepare the DC vaccine, it would not be surprising that, at least in a subset of patients, these cytokines support the differentiation of DC toward an immunosuppressive TEM-8 + phenotype rather than the more immunogenic and clinically active phenotype.…”

Section: Background and Rationalementioning

confidence: 99%

Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised “proof-of-principle” phase II study

Rosa

Ridolfi

et al. 2014

J Transl Med

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BackgroundVaccination with dendritic cells (DC) loaded with tumor antigens elicits tumor-specific immune responses capable of killing cancer cells without inducing meaningful side-effects. Patients with advanced melanoma enrolled onto our phase II clinical studies have been treated with autologous DC loaded with autologous tumor lysate/homogenate matured with a cytokine cocktail, showing a clinical benefit (PR + SD) in 55.5% of evaluable cases to date. The beneficial effects of the vaccine were mainly restricted to patients who developed vaccine-specific immune response after treatment. However, immunological responses were only induced in about two-thirds of patients, and treatments aimed at improving immunological responsiveness to the vaccine are needed.Methods/DesignThis is a phase II, “proof-of-principle”, randomized, open-label trial of vaccination with autologous DC loaded with tumor lysate or homogenate in metastatic melanoma patients combined with immunomodulating RT and/or preleukapheresis IFN-α. All patients will receive four bi-weekly doses of the vaccine during the induction phase and monthly doses thereafter for up to a maximum of 14 vaccinations or until confirmed progression. Patients will be randomized to receive:(1.) three daily doses of 8 Gy up to 12 Gy radiotherapy delivered to one non-index metastatic field between vaccine doses 1 and 2 and, optionally, between doses 7 and 8, using IMRT-IMAT techniques;(2.) daily 3 MU subcutaneous IFN-α for 7 days before leukapheresis;(3.) both 1 and 2;(4.) neither 1 nor 2.At least six patients eligible for treatment will be enrolled per arm. Daily 3 MU IL-2 will be administered subcutaneously for 5 days starting from the second day after each vaccine dose. Serial DTH testing and blood sampling to evaluate treatment-induced immune response will be performed. Objective response will be evaluated according to immune-related response criteria (irRC).DiscussionBased upon the emerging role of radiotherapy as an immunologic modifier, we designed a randomized phase II trial adding radiotherapy and/or preleukapheresis IFN-α to our DC vaccine in metastatic melanoma patients. Our aim was to find the best combination of complementary interventions to enhance anti-tumor response induced by DC vaccination, which could ultimately lead to better survival and milder toxicity.

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Section: Background and Rationalementioning

confidence: 99%

Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised “proof-of-principle” phase II study

Rosa

Ridolfi

et al. 2014

J Transl Med

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“…immature DCs (Bharadwaj et al 2007;Motta et al 2010;Sallusto and Lanzavecchia 1994). The inhibition of DCs development may be a way to ensure tumour cell survival, as the immune response becomes compromised (Motta et al 2010). Indeed, it was found that IL-1b and PGE 2 produced by tumour cells inhibited the Mo differentiation into immature DCs (Motta et al 2010;Sombroek et al 2002).…”

Section: Morphology Phenotype and Cd83mentioning

confidence: 99%

“…DCs (Kalinski et al 1998). Although the aforementioned cytokines were capable of inducing DCs maturation, they inhibited DCs differentiation from Mo (Motta et al 2010;Sallusto and Lanzavecchia 1994;Sombroek et al 2002). Addition of TNF-a, IL-1b or IL-6 to Mo cultures prevented the loss of CD14 as well as the appearance of CD1a molecules, and hence suppressed the in vitro generation of CD14 -CD1a…”

Section: Morphology Phenotype and Cd83mentioning

confidence: 99%

“…The inhibition of DCs development may be a way to ensure tumour cell survival, as the immune response becomes compromised (Motta et al 2010). Indeed, it was found that IL-1b and PGE 2 produced by tumour cells inhibited the Mo differentiation into immature DCs (Motta et al 2010;Sombroek et al 2002). Also, IL-6 secreted by human pancreatic cancer cells suppressed the generation of DCs from Mo via aberrant activation of signal transducer and activator of transcription 3, which may represent a novel target for the prevention of unwanted immune responses in autoimmune diseases through the control of DCs differentiation (Bharadwaj et al 2007;Park et al 2004).…”

Section: Morphology Phenotype and Cd83mentioning

confidence: 99%

Section: Morphology Phenotype and Cd83mentioning

confidence: 99%

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Generation of functional monocyte-derived fast dendritic cells suitable for clinical application in the absence of interleukin-6

Ramadan

2011

Cytotechnology

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To develop dendritic cells (DCs)-based immunotherapy for cancer patients, it is necessary to have a standardized, reproducible, fast, and easy to use protocol for in vitro generation of fully functional DCs. Recently, a new strategy was described for differentiation and maturation of human monocyte (Mo)-derived fast-DCs with full T cell stimulatory capacity within only 48-72 h of in vitro culture. Interleukin (IL)-6 plus tumour necrosis factor (TNF)-a, IL-1b, and prostaglandin (PG)-E 2 were used in this strategy to induce maturation of the generated DCs. The present study further modifies this strategy by excluding IL-6 from the cytokines cocktail used for DCs maturation. The results showed that maturation of fast-DCs without IL-6 did not significantly alter the morphology, phenotype and the yield of mature DCs (P [ 0.05, compared with those generated with IL-6). Moreover, fast-DCs generated without IL-6 are functional antigen presenting cells, have the ability to induce tetanus toxoid-specific autologous T cell proliferation, and are suitable for gene delivery through adenoviral vector transduction as those generated with IL-6 (P [ 0.05). In conclusion, the present study proves that fully mature and functional Mo-derived fast-DCs can be generated in vitro without adding IL-6, which not only reduces the number of required recombinant cytokines, but may also resemble DCs development in vivo more closely.

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Modulation of cytokine production by monocytes and developing‐dendritic cells under the influence of leukemia and lymphoma cell products

Motta

Rumjanek

2020

Cell Biology International

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Cytokines and other soluble factors released by tumor cells play an important role in modulating immune cells to favor tumor development. Monocyte differentiation into macrophages or dendritic cells (DCs) with specific phenotypes is deeply affected by tumor signals and understanding this context is paramount to prevent and propose new therapeutic possibilities. Hence, we developed a study to better describe the modulatory effects of leukemia and lymphoma cell products on human monocytes and monocyte-derived DCs secretion of cytokines such as interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-6, and IL-12. Except with the promyelocytic leukemia cell supernatants (HL-60), the other two tumor supernatants (chronic myeloid leukemia, K562 and Burkitt lymphoma, DAUDI) increased both TNF-α and IL-1β production by monocytes and monocytes undergoing differentiation. This effect was neither explained by alterations of cell number in culture nor by the high amount of vascular endothelial growth factor (VEGF) present in the tumor supernatants. Moreover, all supernatants used were able to induce drastic reduction of IL-12 secretion by cells induced to activation, suggesting a negative interference with Th1 antitumoral responses that should be a huge advantage for tumor progression.

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Leukemic cell products down-regulate human dendritic cell differentiation

Cited by 12 publications

References 31 publications

Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised “proof-of-principle” phase II study

Vaccination with autologous dendritic cells loaded with autologous tumor lysate or homogenate combined with immunomodulating radiotherapy and/or preleukapheresis IFN-α in patients with metastatic melanoma: a randomised “proof-of-principle” phase II study

Generation of functional monocyte-derived fast dendritic cells suitable for clinical application in the absence of interleukin-6

Modulation of cytokine production by monocytes and developing‐dendritic cells under the influence of leukemia and lymphoma cell products

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