Knockdown of the interleukin-6 receptor alpha chain of dendritic cell vaccines enhances the therapeutic potential against IL-6 producing tumors

Hwang, Wonchan; Jung, Keunok; Jeon, Youkyoung; Yun, Shik; Kim, Tae Woo; Choi, Inhak

doi:10.1016/j.vaccine.2010.10.027

Cited by 13 publications

(15 citation statements)

References 28 publications

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“…On the other hand, we found that HIF-1 alpha overexpression induces higher expression IL6 , a known negative regulator of DC differentiation and function [ 24 , 25 ]. Enhanced expression of IL6 has also been shown in hypoxia-conditioned MSCs from bone marrow [ 26 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of hypoxia-inducible factor 1 alpha improves immunomodulation by dental mesenchymal stem cells

et al. 2017

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BackgroundHuman dental mesenchymal stem cells (MSCs) are considered as highly accessible and attractive MSCs for use in regenerative medicine, yet some of their features are not as well characterized as other MSCs. Hypoxia-preconditioning and hypoxia-inducible factor 1 (HIF-1) alpha overexpression significantly improves MSC therapeutics, but the mechanisms involved are not fully understood. In the present study, we characterize immunomodulatory properties of dental MSCs and determine changes in their ability to modulate adaptive and innate immune populations after HIF-1 alpha overexpression.MethodsHuman dental MSCs were stably transduced with green fluorescent protein (GFP-MSCs) or GFP-HIF-1 alpha lentivirus vectors (HIF-MSCs). A hypoxic-like metabolic profile was confirmed by mitochondrial and glycolysis stress test. Capacity of HIF-MSCs to modulate T-cell activation, dendritic cell differentiation, monocyte migration, and polarizations towards macrophages and natural killer (NK) cell lytic activity was assessed by a number of functional assays in co-cultures. The expression of relevant factors were determined by polymerase chain reaction (PCR) analysis and enzyme-linked immunosorbent assay (ELISA).ResultsWhile HIF-1 alpha overexpression did not modify the inhibition of T-cell activation by MSCs, HIF-MSCs impaired dendritic cell differentiation more efficiently. In addition, HIF-MSCs showed a tendency to induce higher attraction of monocytes, which differentiate into suppressor macrophages, and exhibited enhanced resistance to NK cell-mediated lysis, which supports the improved therapeutic capacity of HIF-MSCs. HIF-MSCs also displayed a pro-angiogenic profile characterized by increased expression of CXCL12/SDF1 and CCL5/RANTES and complete loss of CXCL10/IP10 transcription.ConclusionsImmunomodulation and expression of trophic factors by dental MSCs make them perfect candidates for cell therapy. Overexpression of HIF-1 alpha enhances these features and increases their resistance to allogenic NK cell lysis and, hence, their potential in vivo lifespan. Our results further support the use of HIF-1 alpha-expressing dental MSCs for cell therapy in tissue injury and immune disorders.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0659-2) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Overexpression of hypoxia-inducible factor 1 alpha improves immunomodulation by dental mesenchymal stem cells

et al. 2017

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“…It has been shown that the crosstalk between MM-cells and MSCs mediated by toll-like receptor 4 (TRL4) signaling transforms MSCs into a "malignant" phenotype, which promotes tumor growth and immune escape [27]. The MM-conditioned MSCs have been shown to suppress T-cell activation and proliferation, impair DC maturation and induce Tregs via the secretion of several factors, including IL-6, TGF-β, IL-10, PGE2, and upregulated expression of several surface molecules such as VCAM-1, intracellular adhesion molecule-1 (ICAM-1) and CD40 [27][28][29][30][31][32]. Additionally, MSCs can exert their immunomodulatory activities by the secretion of extracellular vesicles [33,34].…”

Section: Immunosuppression and Immune Exhaustion In Bone Marrow Micromentioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells.

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“…Therefore, tumor-induced p-STAT-3 in DC can be seen as a promising target for colon cancer immunotherapy. In this context, knocking-down the IL-6 receptor α-chain of DC vaccines significantly enhanced the frequency of tumor-specific CD8+ CTL-producing effector molecules such as IFN-γ, TNF, FasL, perforin, and granzyme B, and generated more CD8+ memory T cells, leading to the substantially prolonged survival of cytotoxic lymphocytes (Tc1) tumor-bearing mice (Hwang et al, 2010). …”

Section: Il-6 and Pghs-2 (Cox-2)mentioning

confidence: 99%

Chronic Inflammation in Cancer Development

Multhoff¹,

Molls²,

Radons³

2012

Front. Immun.

428

343

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Chronic inflammatory mediators exert pleiotropic effects in the development of cancer. On the one hand, inflammation favors carcinogenesis, malignant transformation, tumor growth, invasion, and metastatic spread; on the other hand inflammation can stimulate immune effector mechanisms that might limit tumor growth. The link between cancer and inflammation depends on intrinsic and extrinsic pathways. Both pathways result in the activation of transcription factors such as NF-κB, STAT-3, and HIF-1 and in accumulation of tumorigenic factors in tumor and microenvironment. STAT-3 and NF-κB interact at multiple levels and thereby boost tumor-associated inflammation which can suppress anti-tumor immune responses. These factors also promote tumor growth, progression, and metastatic spread. IL-1, IL-6, TNF, and PGHS-2 are key mediators of an inflammatory milieu by modulating the expression of tumor-promoting factors. In this review we concentrate on the crucial role of pro-inflammatory mediators in inflammation-driven carcinogenesis and outline molecular mechanisms of IL-1 signaling in tumors. In addition, we elucidate the dual roles of stress proteins as danger signals in the development of anti-cancer immunity and anti-apoptotic functions.

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Knockdown of the interleukin-6 receptor alpha chain of dendritic cell vaccines enhances the therapeutic potential against IL-6 producing tumors

Cited by 13 publications

References 28 publications

Overexpression of hypoxia-inducible factor 1 alpha improves immunomodulation by dental mesenchymal stem cells

Overexpression of hypoxia-inducible factor 1 alpha improves immunomodulation by dental mesenchymal stem cells

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Chronic Inflammation in Cancer Development

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