Expression of a Soluble TGF-β Receptor by Tumor Cells Enhances Dendritic Cell/Tumor Fusion Vaccine Efficacy

Zhang, Min; Berndt, Bradford E.; Chen, Jianjun; Kao, John Y.

doi:10.4049/jimmunol.181.5.3690

Cited by 34 publications

(19 citation statements)

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“…In this light, DC genetically engineered to secrete a VEGF/vascular permeability factor decoy receptor that neutralizes soluble VEGF and precludes signaling in DC resulted in increased expression of costimulatory molecules and proinflammatory cytokines/chemokines by DC and improved CTL activity and anti-tumor immune control in a murine colon cancer model (157). Similar improvements in the efficacy of an exogenous DC vaccine were observed following neutralization of tumor-derived TGFβ (158). Alternatively, other approaches for enhancing exogenous DC-induced anti-tumor immune responses aim at blocking either the immunosuppressive mediators expressed by tumor-altered DC or the targets of these mediators expressed on other immune cells.…”

Section: Immunotherapeutic Strategies For Interfering With Tumor-assomentioning

confidence: 65%

Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity

Hargadon¹

2013

Front. Immunol.

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Dendritic cells (DC) are key regulators of both innate and adaptive immunity, and the array of immunoregulatory functions exhibited by these cells is dictated by their differentiation, maturation, and activation status. Although a major role for these cells in the induction of immunity to pathogens has long been appreciated, data accumulated over the last several years has demonstrated that DC are also critical regulators of anti-tumor immune responses. However, despite the potential for stimulation of robust anti-tumor immunity by DC, tumor-altered DC function has been observed in many cancer patients and tumor-bearing animals and is often associated with tumor immune escape. Such dysfunction has significant implications for both the induction of natural anti-tumor immune responses as well as the efficacy of immunotherapeutic strategies that target endogenous DC in situ or that employ exogenous DC as part of anti-cancer immunization maneuvers. In this review, the major types of tumor-altered DC function will be described, with emphasis on recent insights into the mechanistic bases for the inhibition of DC differentiation from hematopoietic precursors, the altered programing of DC precursors to differentiate into myeloid-derived suppressor cells or tumor-associated macrophages, the suppression of DC maturation and activation, and the induction of immunoregulatory DC by tumors, tumor-derived factors, and tumor-associated cells within the milieu of the tumor microenvironment. The impact of these tumor-altered cells on the quality of the overall anti-tumor immune response will also be discussed. Finally, this review will also highlight questions concerning tumor-altered DC function that remain unanswered, and it will address factors that have limited advances in the study of this phenomenon in order to focus future research efforts in the field on identifying strategies for interfering with tumor-associated DC dysfunction and improving DC-mediated anti-tumor immunity.

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Section: Immunotherapeutic Strategies For Interfering With Tumor-assomentioning

confidence: 65%

Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity

Hargadon¹

2013

Front. Immunol.

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“…An adenovirus encoding human TGF-β receptor type II fused to the Fc region of human IgM was used to express a soluble form of the neutralizing TGF-β receptor (TGF-β-R), which has been shown to cross-react with mouse TGF-β [21]. We have previously demonstrated that the soluble TGF-β-R neutralizes TGF-β produced by tumor cells [22]. A CT26 cell line that hence produces below physiologic levels of TGF-β (CT26-TGF-β-R) was generated using a retrovirus that expressed TGF-β-R and the neomycin resistance gene.…”

Section: Methodsmentioning

confidence: 99%

“…This modified ELISA estimates the TGF-β-R concentration by measuring the amount of TGF-β bound to TGF-β-R, and has previously been described in further detail [22]. …”

Section: Methodsmentioning

confidence: 99%

The effect of CT26 tumor-derived TGF-β on the balance of tumor growth and immunity

et al. 2017

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Introduction TGF-β is an important target for many cancer therapies under development. In addition to suppressing anti-tumor immunity, it has pleiotropic direct pro- and anti-tumor effects. The actions of increased endogenous TGF-β production remain unclear, and may affect the outcomes of anti-TGF-β cancer therapy. We hypothesize that tumor-derived TGF-β (td-TGF-β) plays an important role in maintaining tumor remission by controlling tumor proliferation in vivo, and that decreasing td-TGF-β in the tumor microenvironment will result in tumor progression. The aim of this study was to examine the effect of TGF-β in the tumor microenvironment on the balance between its anti-proliferative and immunosuppressive effects. Methods A murine BALB/c spontaneous colon adenocarcinoma cell line (CT26) was genetically engineered to produce increased active TGF-β (CT26-TGF-β), a dominant-negative soluble TGF-β receptor (CT26-TGF-β-R), or the empty neomycin cassette as control (CT26-neo). In vitro proliferation rates were measured. For in vivo studies, the three cell lines were injected into syngeneic BALB/c mice, and tumor growth was measured over time. Immunodeficient BALB/c nude mice were used to investigate the role of T and B cells. Results In vitro, CT26-TGF-β-R and CT26-TGF-β cells showed increased and suppressed proliferation, respectively, compared to control (CT26-neo), confirming TGF-β has direct anti-tumor effects. In vivo, we found that CT26-TGF-β-R cells displayed slower growth compared to control, likely secondary to reduced suppression of anti-tumor immunity, as this effect was ablated in immunodeficient BALB/c nude mice. However, CT26-TGF-β cells (excess TGF-β) exhibited rapid early growth compared to control, but later failed to progress. The same pattern was shown in immunodeficient BALB/c nude mice, suggesting the effect on tumor growth is direct, with minimal immune system involvement. There was minimal effect on systemic antitumor immunity as determined by peripheral antigen-specific splenocyte type 1 cytokine production and tumor growth rate of CT26-neo on the contralateral flank of the same mice. Conclusion Although TGF-β has opposing effects on tumor growth, this study showed that excessive td-TGF-β in the tumor microenvironment renders the tumor non-proliferative. Depleting excess td-TGF-β may release this endogenous tumor suppressive mechanism, thus triggering the progression of the tumor. Therefore, our findings support cautions against using anti-TGF-β strategies in treating cancer, as this may tip the balance of anti-immunity vs. anti-tumor effects of TGF-β, leading to tumor progression instead of remission.

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“…A series of studies demonstrated the efficacy of autologous DCs pulsed with defined TAAs as therapeutic cancer vaccines in preclinical models (Sas et al , 2008; Zhang et al , 2008). Although not as effective as in preclinical models, DCs pulsed with TAAs were shown to induce durable anti-tumor responses with demonstrable clinical efficacy.…”

Section: Dendritic Cell-based Cancer Vaccinesmentioning

confidence: 99%

ProtEx™ technology for the generation of novel therapeutic cancer vaccines

Schabowsky

Sharma

Madireddi

et al. 2009

Experimental and Molecular Pathology

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Therapeutic vaccines present an attractive alternative to conventional treatments for cancer. However, tumors have evolved various immune evasion mechanisms to modulate innate, adaptive, and regulatory immunity for survival. Therefore, successful vaccine formulations may require a non-toxic immunomodulator or adjuvant that not only induces/stimulates innate and adaptive tumor-specific immune responses, but also overcome immune evasion mechanisms. Given the paramount role costimulation plays in modulating innate, adaptive, and regulatory immune responses, costimulatory ligands may serve as effective immunomodulating components of therapeutic cancer vaccines. Our laboratory has developed a novel technology designated as ProtEx™ that allows for the generation of recombinant costimulatory ligands with potent immunomodulatory activities and the display of these molecules on the cell surface in a rapid and efficient manner as a practical and safe alternative to gene therapy for immunomodulation. Importantly, the costimulatory ligands not only function when displayed on tumor cells, but also as soluble proteins that can be used as immunomodulatory components of conventional vaccine formulations containing tumor-associated antigens (TAAs). We herein discuss the application of the ProtEx™ technology to the development of effective cell-based as well as cell-free conventional therapeutic cancer vaccines.Current treatment of primary tumors usually involves a combination of surgery, radiotherapy, and chemotherapy. These treatment modalities often are associated with adverse side effects arising from lack of specificity for tumors and, importantly, frequently fail to eliminate residual and micrometastatic tumors, which can lead to recurrences (Kasimir-Bauer, 2001). It is therefore vital to develop tumor-specific therapies that not only eliminate primary tumors but also micrometastatic tumor cells, and prevent recurrences. In this context, cancer vaccines may serve an ideal treatment due to their specificity for tumor cells and long lasting immunological memory that may safeguard against recurrences.

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Expression of a Soluble TGF-β Receptor by Tumor Cells Enhances Dendritic Cell/Tumor Fusion Vaccine Efficacy

Cited by 34 publications

References 35 publications

Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity

Tumor-Altered Dendritic Cell Function: Implications for Anti-Tumor Immunity

The effect of CT26 tumor-derived TGF-β on the balance of tumor growth and immunity

ProtEx™ technology for the generation of novel therapeutic cancer vaccines

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