IFN-alpha in the Generation of Dendritic Cells for Cancer Immunotherapy

Santini, Stefano M.; Lapenta, Caterina; Santodonato, Laura; D’Agostino, Giuseppina; Belardelli, Filippo; Ferrantini, Maria

doi:10.1007/978-3-540-71029-5_14

Cited by 54 publications

(53 citation statements)

References 80 publications

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“…7,8 Although IFN-a was long thought to function mainly by suppressing tumor cell proliferation in vivo, more recently it has been established that type I IFNs have important roles in regulating the innate and adaptive arms of the immune system: upregulation of major histocompatibility complex class I gene, promotion of the priming and survival of T cells, enhancement of humoral immunity, increase of the cytotoxic activity of natural killer (NK) cells and CD8 + T cells and activation of dendritic cells (DCs). 9,10 We also reported that in addition to the direct cytotoxicity in the injected site, intratumoral IFN-a gene transfer elicits a systemic tumor-specific immunity in several animal models. 11,12 Furthermore, our data showed that, because of the effective induction of antitumor immunity and the lower toxicity, an intratumoral route of the IFN vector is superior to an intravenous administration.…”

Section: Introductionmentioning

confidence: 96%

In vivo delivery of interferon-α gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts

Narumi

Udagawa²,

Kondo³

et al. 2011

Gene Ther

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T cells recognize tumor-associated antigens under the condition of lymphopenia-induced homeostatic proliferation (HP); however, HP-driven antitumor responses gradually decay in association with tumor growth. Type I interferon (IFN) has important roles in regulating the innate and adaptive immune system. In this study we examined whether a tumor-specific immune response induced by IFN-a could enhance and sustain HP-induced antitumor immunity. An intratumoral IFN-a gene transfer resulted in marked tumor suppression when administered in the early period of syngeneic hematopoietic stem cell transplantation (synHSCT), and was evident even in distant tumors that were not transduced with the IFN-a vector. The intratumoral delivery of the IFN-a gene promoted the maturation of CD11c + cells in the tumors and effectively augmented the antigen-presentation capacity of the cells. An analysis of the cytokine profile showed that the CD11c + cells in the treated tumors secreted a large amount of immune-stimulatory cytokines including interleukin (IL)-6. The CD11c + cells rescued effector T-cell proliferation from regulatory T-cell-mediated suppression, and IL-6 may have a dominant role in this phenomenon. The intratumoral IFN-a gene transfer creates an environment strongly supporting the enhancement of antitumor immunity in reconstituted lymphopenic recipients through the induction of tumor-specific immunity and suppression of immunotolerance.

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Section: Introductionmentioning

confidence: 96%

In vivo delivery of interferon-α gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts

Narumi

Udagawa²,

Kondo³

et al. 2011

Gene Ther

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“…In particular, IFN-␣ has been shown to act as a potent inducer of the rapid differentiation of human monocytes into highly activated and partially mature dendritic cells (DCs), known as IFN-DCs. 1 We demonstrated previously that human monocytes exposed to granulocyte macrophage colony-stimulating factor (GM-CSF) and IFN-␣ are rapidly induced to express a set of membrane molecules involved in antigen (Ag) presentation and T-cell costimulation, as well as to strongly promote T helper (Th)-1 response and CD8 ϩ T cell cross-priming. 2 Moreover, IFN-DCs were shown to cross-present very efficiently low amounts of nonstructural-3 protein (NS3) of hepatitis C virus (HCV) to a specific CD8 ϩ T cell clone, even in the absence of CD4 ϩ T-cell help.…”

mentioning

confidence: 99%

IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

Spadaro

Lapenta

Donati

et al. 2012

Blood

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IntroductionOver the past years, it has become apparent that type-I interferons (IFNs) affect adaptive immunity through their effects on monocytes. In particular, IFN-␣ has been shown to act as a potent inducer of the rapid differentiation of human monocytes into highly activated and partially mature dendritic cells (DCs), known as IFN-DCs. 1 We demonstrated previously that human monocytes exposed to granulocyte macrophage colony-stimulating factor (GM-CSF) and IFN-␣ are rapidly induced to express a set of membrane molecules involved in antigen (Ag) presentation and T-cell costimulation, as well as to strongly promote T helper (Th)-1 response and CD8 ϩ T cell cross-priming. 2 Moreover, IFN-DCs were shown to cross-present very efficiently low amounts of nonstructural-3 protein (NS3) of hepatitis C virus (HCV) to a specific CD8 ϩ T cell clone, even in the absence of CD4 ϩ T-cell help. 2 The cross-presentation efficiency of DCs is not dictated solely by their Ag capture capability 3 ; it also is affected by critical factors such as (1) the route of Ag uptake, (2) acidification-sensitive Ag degradation in endosomal-lysosomal compartments, and (3) Ag entry into the major histocompatibility complex class-I (MHC-I) pathway. [4][5][6][7][8] At present, 4 nonmutually exclusive models have been proposed to explain cross-presentation. [8][9][10] In the canonical cytosolic pathway, endocytosed Ags are translocated into the cytosol, where they are degraded by the proteasome, and then the antigenic peptides are transported into the lumen of the endoplasmic reticulum (ER) by the transporters associated with Ag processing (TAPs), 9,10 or alternatively, reimported from the cytoplasm into the early endosomes and loaded onto endosomal 12 According to a less well-defined TAP-and proteasomeindependent endosomal pathway, Ags can be processed by endosomal proteases and loaded onto MHC-I molecules directly within early and late endosomes and lysosomes. [13][14][15] An additional model involves the delivery of components of the ER to endocytic organelles or the transport of incoming Ags to the ER. [16][17][18] Here, we have investigated the mechanisms underlying the superior efficiency of IFN-DCs in the cross-presentation of soluble proteins, by studying (1) the Ag uptake and trafficking to the class-I processing pathway, (2) the maturation kinetic of the organelles containing the internalized proteins, (3) the Ag stability within endosomes, and (4) the Ag processing and cross-presentation to specific CD8 ϩ T cells. The results reveal that IFN-DCs exhibit a delayed endosomal acidification associated with a prolonged Ag survival and retention in the early endosomal compartment, as well as with Ag trafficking to recycling pathways. In IFN-DCs, both early and recycling endosomal compartments serve as important stores of MHC-I molecules, allowing rapid presentation of exogenous Ags. These findings provide novel mechanistic insight into the cross-presentation efficiency of IFN-DCs and underscore the potential advantage of using these cellula...

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“…More recent studies have revealed new immunomodulatory effects of IFN-α, including activities on T cells and dendritic cells. Overall, therapeutic strategies based on IFN-α include the use of these cytokines in vivo as immune adjuvants of cancer vaccines or their use ex vivo to generate DC-based vaccines and the combination of certain chemotherapy regimens with IFN-α [442][443][444]. Interferon-γ (IFN-γ) is a cytokine that acts on cell-surface receptors, activating transcription of genes that increase tumor immunogenicity, disrupt proliferative mechanisms and inhibit tumor angiogenesis.…”

Section: Chemokines and Cytokinesmentioning

confidence: 99%

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

Schwendener¹,

Mete²

2013

Frontiers in Clinical Drug Research - Anti-Cancer Agents

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Solid tumors grow within a complex microenvironment composed of diverse cell types such as fibroblasts, endothelial cells, mast cells, macrophages and immune cells that are attracted by tumor cell derived factors and embedded in an extracellular matrix. Molecular and cellular interactions between epithelial cells and cells surrounding the tumor stroma promote growth, invasion and spread of tumors. To delay or impede tumor growth, the tumor microenvironment (TME) is increasingly being explored as a potential therapeutic target for which novel strategies are developed. lt;/pgt;lt;pgt; This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed. This article reviews how key interactions between tumor cells and surrounding mesenchymal and immune cells in the TME can promote tumor progression and it highlights cellular and molecular elements that might represent novel therapeutic targets. Special emphasis is given on therapies targeted towards tumor-associated macrophages. As main class of drugs the bisphosphonates are covered with their properties to repolarize a pro-tumorigenic, immunosuppressive environment to a tumor growth inhibiting and immunocompetent microenvironment. Properties and advantages of liposome-encapsulated bisphosphonates as macrophage depleting or modulating agents as well as the latest developments towards clinical applications of compounds targeting cellular and molecular components of the TME are described and reviewed.

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IFN-alpha in the Generation of Dendritic Cells for Cancer Immunotherapy

Cited by 54 publications

References 80 publications

In vivo delivery of interferon-α gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts

In vivo delivery of interferon-α gene enhances tumor immunity and suppresses immunotolerance in reconstituted lymphopenic hosts

IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing

A New Approach to Cancer Therapy: The Tumor Microenvironment as Target

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