Intratumoral Injection of CpG Oligonucleotides Induces the Differentiation and Reduces the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells

Shirota, Yuko; Shirota, Hidekazu; Klinman, Dennis M.

doi:10.4049/jimmunol.1101304

Cited by 217 publications

(228 citation statements)

References 39 publications

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“…While we previously showed that tumorinfiltrating monocytic MDSCs are NP þ , delivering our model cancer vaccine to the tdLN decreased the number of tumorresident Gr1 int MDSCs, which are described as monocytic and the most immunosuppressive subset, and led to MDSC maturation, thus making them less suppressive (21,36,48). CpG has been shown to affect the phenotype of MDSCs, especially monocytic MDSCs, in tumor-bearing mice, but at much higher CpG doses than we used here (32,49). We believe that our findings may be due to an effect of CpG on MDSCs and to a change in the cellular and cytokine environment in the tumor following immunization.…”

Section: Discussionmentioning

confidence: 89%

“…We used the TLR9-ligand CpG as adjuvant for its Th1-skewing properties (12) and ability to boost antitumor immunity (30)(31)(32). B16-F10-bearing mice were immunized intradermally in all four footpads 4, 7, 11, and 15 days after inoculation with 40 mg TRP-2 180-188 and 4 mg CpG conjugated onto nanoparticles (NP-TRP-2 þ NP-CpG) or in soluble form (TRP-2 þ CpG; Fig.…”

Section: Nanoparticle Conjugation Enhances Cell Targeting and Therapementioning

confidence: 99%

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Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Jeanbart

Ballester

Titta

et al. 2014

Cancer Immunology Research

172

133

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The sentinel or tumor-draining lymph node (tdLN) serves as a metastatic niche for many solid tumors and is altered via tumor-derived factors that support tumor progression and metastasis. tdLNs are often removed surgically, and therapeutic vaccines against tumor antigens are typically administered systemically or in nontumor-associated sites. Although the tdLN is immune-suppressed, it is also antigen experienced through drainage of tumor-associated antigens (TAA), so we asked whether therapeutic vaccines targeting the tdLN would be more or less effective than those targeting the non-tdLN. Using LN-targeting nanoparticle (NP)-conjugate vaccines consisting of TAA-NP and CpG-NP, we compared delivery to the tdLN versus non-tdLN in two different cancer models, E.G7-OVA lymphoma (expressing the nonendogenous TAA ovalbumin) and B16-F10 melanoma. Surprisingly, despite the immune-suppressed state of the tdLN, tdLN-targeting vaccination induced substantially stronger cytotoxic CD8 þ T-cell responses, both locally and systemically, than non-tdLN-targeting vaccination, leading to enhanced tumor regression and host survival. This improved tumor regression correlated with a shift in the tumor-infiltrating leukocyte repertoire toward a less suppressive and more immunogenic balance. Nanoparticle coupling of adjuvant and antigen was required for effective tdLN targeting, as nanoparticle coupling dramatically increased the delivery of antigen and adjuvant to LN-resident antigen-presenting cells, thereby increasing therapeutic efficacy. This work highlights the tdLN as a target for cancer immunotherapy and shows how its antigen-experienced but immune-suppressed state can be reprogrammed with a targeted vaccine yielding antitumor immunity. Cancer Immunol Res; 2(5); 436-47. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 89%

Section: Nanoparticle Conjugation Enhances Cell Targeting and Therapementioning

confidence: 99%

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Jeanbart

Ballester

Titta

et al. 2014

Cancer Immunology Research

172

133

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“…In addition, complement factor 4 produced by myeloid cells may regulate spontaneous GC reactions in self-reactive B cell receptor transgenic mice [14]. We therefore suggest that the chronic inflammatory milieu developing in female (NZB x NZW)F1 mice affect a population of regulatory neutrophils (Nregs) either via the induction of apoptosis (or maybe even NETosis) [4,83] or via the induction of a differentiation program driving the development of non-immunosuppressive cells such as dendritic cells, macrophages or mature neutrophils, as previously suggested [83][84][85].…”

Section: Anti-inflammatory Properties Of Neutrophils In Lupusmentioning

confidence: 92%

Pro- and Anti-inflammatory Neutrophils in Lupus

Der¹,

Trigunaite²,

Khan³

et al. 2014

J Clin Cell Immunol

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A hallmark of SLE is the presence of elevated levels of circulating anti-nuclear autoantibodies specific towards chromatin, histones or dsDNA. Understanding the regulation of antibody production is therefore of utmost importance in understanding lupus pathogenesis. Spearheaded by the identification of accumulating immunosuppressive neutrophils in cancer patients, the nature and function of neutrophils have expanded from a uniform pro-inflammatory cell population to a heterogeneous population of cells with pro-inflammatory or immunosuppressive capacities. While much is known about pro-inflammatory neutrophils and the likely pathogenic function of such cells in lupus, a potential role for immunosuppressive neutrophils in protecting genetically predisposed individuals has only recently emerged. For example, SLE-derived neutrophils spontaneously produce type I interferons (IFNα), strongly associated with disease development, release chromatin-containing neutrophil extracellular traps (NETs), potentially functioning as a source of nuclear auto-antigen, and may activate B cells in a T cell independent fashion. In contrast, levels and functions of regulatory neutrophils (Nregs) involved in T celldependent B cell differentiation and germinal center reactions, are dysregulated in female lupus-prone mice during disease development. Here we review data supporting a role for both pro-and anti-inflammatory neutrophils in lupus.

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“…Hence, injection of tumor cells in combination with CD11b + Gr1 + cells in mice prompt tumor growth [249]. Accordingly, depletion of Gr1 + cells in tumor-bearing mice leads to delayed tumor growth, suggesting MDSC as potential targets for anti-cancer therapy [250][251][252][253][254][255][256]. A report by Youn and colleagues indicated that CD11b + Gr1 + cells from naïve tumor-free mice are not immune suppressive [243].…”

Section: Myeloid Derived Suppressor Cells (Mdsc)mentioning

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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Intratumoral Injection of CpG Oligonucleotides Induces the Differentiation and Reduces the Immunosuppressive Activity of Myeloid-Derived Suppressor Cells

Cited by 217 publications

References 39 publications

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Enhancing Efficacy of Anticancer Vaccines by Targeted Delivery to Tumor-Draining Lymph Nodes

Pro- and Anti-inflammatory Neutrophils in Lupus

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

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