Ex vivo recovery and activation of dysfunctional, anergic, monocyte-derived dendritic cells from patients with operable breast cancer: critical role of IFN-alpha

Satthaporn, Sukchai; Aloysius, Mark M.; Robins, R. A.; Verma, Chandan; Chuthapisith, Suebwong; McKechnie, A.; El-Sheemy, Mohamad; Vassanasiri, Wichai; Valerio, D; Clark, David W.; Jibril, Jibril A; Eremin, O.

doi:10.1186/1471-2172-9-32

Cited by 6 publications

(10 citation statements)

References 67 publications

(70 reference statements)

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“…26 It has been suggested that rhIFNα 2 b plays important roles in antitumor and antiviral activity and regulation of the immune system. 3,[8][9][10][11][12][13][14][15][16] The mechanism of the antitumor effect is not completely clear yet. However, studies have suggested it might inhibit tumor growth in vivo through tumor cellgrowth inhibition, tumor-cell apoptosis, oncogene-expression restraint, immune-system regulation, and tumor-angiogenesis suppression.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7] Some studies show that IFNα, including IFNα 2 b, is also capable of exerting antitumor effects against HCC, hairy cell leukemia, lymphoma, melanoma, and breast cancer. 3,[8][9][10][11][12][13][14][15][16] However, an extensive clinical trial of IFNα 2 b for HCC was delayed, due to the weak therapeutic effect based on conventional drug-delivery methods. In general, these methods cause rapid degradation of IFNα 2 b in the body and induce severe side effects, due to the systemic distribution of drugs in the body causing bone marrow suppressions and neurologic disorders.…”

Section: Introductionmentioning

confidence: 99%

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Preclinical evaluation of recombinant human IFNα2b-containing magnetoliposomes for treating hepatocellular carcinoma

Ye¹,

Jiao²,

Wu³

et al. 2014

IJN

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Magnetoliposomes are phospholipid vesicles encapsulating magnetic nanoparticles that can be used to encapsulate therapeutic drugs for delivery into specific organs. Herein, we developed magnetoliposomes containing recombinant human IFNα 2 b, designated as MIL, and evaluated this combination’s biological safety and therapeutic effect on both cellular and animal hepatocellular carcinoma models. Our data showed that MIL neither hemolyzed erythrocytes nor affected platelet-aggregation rates in blood. Nitroblue tetrazolium-reducing testing showed that MIL did not change the absolute numbers or phagocytic activities of leukocytes. Acute-toxicity testing also showed that MIL had no devastating effect on mice behaviors. All the results indicated that the nanoparticles could be a safe biomaterial. Pharmacokinetic analysis and tissue-distribution studies showed that MIL maintained stable and sustained drug concentrations in target organs under a magnetic field, helped to increase bioavailability, and reduced administration time. MIL also dramatically inhibited the growth of hepatoma cells. Targeting of MIL in the livers of nude mice bearing human hepatocellular carcinoma showed that MIL significantly reduced the tumor size to 38% of that of the control group. Further studies proved that growth inhibition of cells or tumors was due to apoptosis-signaling pathway activation by human IFNα 2 b.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of recombinant human IFNα2b-containing magnetoliposomes for treating hepatocellular carcinoma

Ye¹,

Jiao²,

Wu³

et al. 2014

IJN

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“…CD86 is constitutively expressed on antigenpresenting cells (APC), whereas CD80 expression is induced upon APC activation. Cancers, including breast cancers (12)(13)(14)(15), show an abundance of immature DCs with impaired capacity to stimulate antitumor immunity (16). In cancer, the main mechanisms of immune evasion resulting in impaired antitumor T-cell response are (i) the lack of expression of costimulatory ligands such as CD80 and CD86 on APCs (8) and (ii) the increased number of T regulatory cells (Treg; ref.…”

Section: Introductionmentioning

confidence: 99%

TIE-2 and VEGFR Kinase Activities Drive Immunosuppressive Function of TIE-2–Expressing Monocytes in Human Breast Tumors

Ibberson

Bron

Guex

et al. 2013

Clinical Cancer Research

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Purpose: Tumor-associated TIE-2-expressing monocytes (TEM) are highly proangiogenic cells critical for tumor vascularization. We previously showed that, in human breast cancer, TIE-2 and VEGFR pathways control proangiogenic activity of TEMs. Here, we examine the contribution of these pathways to immunosuppressive activity of TEMs.Experimental Design: We investigated the changes in immunosuppressive activity of TEMs and gene expression in response to specific kinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEMs to suppress tumor-specific T-cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was done using confocal microscopic images analysis of breast carcinomas.Results: TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEMs can function as antigen-presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells. We show that immunosuppressive activity of TEMs is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells.Conclusions: These results suggest that TEMs are plastic cells that can be reverted from suppressive, proangiogenic cells into cells that are able to mediate an antitumoral immune response.

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“…This was the rationale for choosing to compare TNF-α by itself or in combination with IFN-α as a maturation and activation factor for ex vivo monocyte-derived DCs, instead of the standard Jonuleit's DC maturation cocktail. Our previous work in vitro had demonstrated that monocyte-derived DCs matured with TNF-α and IFN-α were phenotypically and functionally superior to DCs matured with TNF-α alone[ 36 ].…”

Section: Introductionmentioning

confidence: 99%

“…We compared hTERT-specific CD8+T cell responses elicited in vivo between the above two DC preparations. In our previously published work we had shown that this cytokine combination (GM-CSF, IL-4, TNF-α ± IFN-α) was capable of generating DCs in vitro from CD14+ monocytes obtained from healthy individuals and patients with cancer[ 36 ]. These DCs were activated but relatively immature, strongly phagocytic and induced CD8+T cell responses in vitro .…”

Section: Introductionmentioning

confidence: 99%

Generation in vivo of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs

et al. 2009

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BackgroundOptimal techniques for DC generation for immunotherapy in cancer are yet to be established. Study aims were to evaluate: (i) DC activation/maturation milieu (TNF-α +/- IFN-α) and its effects on CD8+ hTERT-specific T cell responses to class I epitopes (p540 or p865), (ii) CD8+ hTERT-specific T cell responses elicited by vaccination with class I alone or both class I and II epitope (p766 and p672)-pulsed DCs, prepared without IFN-α, (iii) association between circulating T regulatory cells (Tregs) and clinical responses.MethodsAutologous DCs were generated from 10 patients (HLA-0201) with advanced cancer by culturing CD14+ blood monocytes in the presence of GM-CSF and IL-4 supplemented with TNF-α [DCT] or TNF-α and IFN-α [DCTI]. The capacity of the DCs to induce functional CD8+ T cell responses to hTERT HLA-0201 restricted nonapeptides was assessed by MHC tetramer binding and peptide-specific cytotoxicity. Each DC preparation (DCT or DCTI) was pulsed with only one type of hTERT peptide (p540 or p865) and both preparations were injected into separate lymph node draining regions every 2–3 weeks. This vaccination design enabled comparison of efficacy between DCT and DCTI in generating hTERT peptide specific CD8+ T cells and comparison of class I hTERT peptide (p540 or p865)-loaded DCT with or without class II cognate help (p766 and p672) in 6 patients. T regulatory cells were evaluated in 8 patients.Results(i) DCTIs and DCTs, pulsed with hTERT peptides, were comparable (p = 0.45, t-test) in inducing peptide-specific CD8+ T cell responses. (ii) Class II cognate help, significantly enhanced (p < 0.05, t-test) peptide-specific CD8+T cell responses, compared with class I pulsed DCs alone. (iii) Clinical responders had significantly lower (p < 0.05, Mann-Whitney U test) T regs, compared with non-responders. 4/16 patients experienced partial but transient clinical responses during vaccination. Vaccination was well tolerated with minimal toxicity.ConclusionAddition of IFN-α to ex vivo monocyte-derived DCs, did not significantly enhance peptide-specific T cell responses in vivo, compared with TNF-α alone. Class II cognate help significantly augments peptide-specific T cell responses. Clinically favourable responses were seen in patients with low levels of circulating T regs.

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Ex vivo recovery and activation of dysfunctional, anergic, monocyte-derived dendritic cells from patients with operable breast cancer: critical role of IFN-alpha

Cited by 6 publications

References 67 publications

Preclinical evaluation of recombinant human IFNα2b-containing magnetoliposomes for treating hepatocellular carcinoma

Preclinical evaluation of recombinant human IFNα2b-containing magnetoliposomes for treating hepatocellular carcinoma

TIE-2 and VEGFR Kinase Activities Drive Immunosuppressive Function of TIE-2–Expressing Monocytes in Human Breast Tumors

Generation in vivo of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs

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Ex vivo recovery and activation of dysfunctional, anergic, monocyte-derived dendritic cells from patients with operable breast cancer: critical role of IFN-alpha

Cited by 6 publications

References 67 publications

Preclinical evaluation of recombinant human IFN&alpha;2b-containing magnetoliposomes for treating hepatocellular carcinoma

Preclinical evaluation of recombinant human IFN&alpha;2b-containing magnetoliposomes for treating hepatocellular carcinoma

TIE-2 and VEGFR Kinase Activities Drive Immunosuppressive Function of TIE-2–Expressing Monocytes in Human Breast Tumors

Generation in vivo of peptide-specific cytotoxic T cells and presence of regulatory T cells during vaccination with hTERT (class I and II) peptide-pulsed DCs

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Preclinical evaluation of recombinant human IFNα2b-containing magnetoliposomes for treating hepatocellular carcinoma

Preclinical evaluation of recombinant human IFNα2b-containing magnetoliposomes for treating hepatocellular carcinoma