Dual T Cell Receptor Expressing CD8+ T Cells with Tumor- and Self-Specificity Can Inhibit Tumor Growth without Causing Severe Autoimmunity

Weinhold, Monika; Sommermeyer, Daniel; Uckert, Wolfgang; Blankenstein, Thomas

doi:10.4049/jimmunol.179.8.5534

Cited by 25 publications

(25 citation statements)

References 47 publications

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“…7) and normal blood glucose levels were measured (data not shown). These results are in agreement with a previous study in which B16-LCMV(gp-33) tumor growth was inhibited in RipOVA low mice via adoptive transfer of CTL with dual-specificity for gp-33 and OVA without the induction of severe diabetes, yet a transient increase in blood glucose levels and inflammatory infiltrates were noted (50). Interestingly, we also observed no signs of melanocyte antigen-specific autoimmunity such as skin depigmentation or uveitis in treated DEREG and DEREG × RipOVA low mice, including those which completely rejected B16-OVA.…”

Section: Combining Selective Foxp3supporting

confidence: 82%

Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma

Klages

Mayer²,

Lahl³

et al. 2010

Cancer Research

234

194

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Section: Combining Selective Foxp3supporting

confidence: 82%

Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma

Klages

Mayer²,

Lahl³

et al. 2010

Cancer Research

234

194

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“…21 We conclude that induction of tumor antigen-specific CD8ϩ T cell tolerance and TCR down-modulation represents an obstacle for future immunotherapies in liver tumors. Possibly, vaccination or adoptive T cell transfer 41 and therapies targeting the organ-specific tumor stroma 42 need to be combined to be successful in patients. These results emphasize the need for preclinical testing in autochthonous tumor models.…”

Section: Discussionmentioning

confidence: 99%

Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation

et al. 2008

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The reason the adaptive immune system fails in advanced liver tumors is largely unclear. To address this question, we have developed a novel murine model that combines c-mycinduced autochthonous tumorigenesis with expression of a cognate antigen, ovalbumin (OVA). When c-myc/OVA transgenic mice were crossed with liver-specific inducer mice, multifocal hepatocellular carcinomas co-expressing OVA developed in a tetracycline-dependent manner with a short latency and 100% penetrance. Transferred OVA-specific T cells, although infiltrating the tumor at high numbers, were hyporesponsive, as evidenced by a lack of in vivo cytotoxicity and interferon gamma production. This allowed the tumor to progress even in the presence of large numbers of antigen-specific T cells and even after vaccination (OVA؉CpG-DNA). Interestingly, T cell receptor down-modulation was observed, which may explain antigen-specific hyporesponsiveness. This model is helpful in understanding liver cancer-specific mechanisms of T cell tolerance and dissection of antigen-specific and nonspecific mechanisms of immunotherapies in the preclinical phase. Clinical observations suggest that the immune system is important in keeping tumor growth under control. [3][4][5] However, the immune system is frequently unable to control tumor burden in patients suffering from advanced cancer arising in solid parenchymatous organs, such as the liver. One reason could be that the liver represents a tolerogenic environment for T cells. 6,7 Another reason could be that tolerance occurs because of a tolerizing microenvironment specific for advanced autochthonous tumors that arise spontaneously and slowly over time. Third, tumor antigen may be transported to lymphatic tissues for induction of cross-tolerance, which has been described as a mechanism of peripheral CD8 ϩ T cell tolerance induction against self-antigens. 8 Recent reports indicate that immune tolerance in spontaneous tumors occurs because of a failure of the adaptive immune system. 9,10 However, the mechanism of tolerance induction in autochthonous tumors remains poorly defined.Tumor antigen-specific immune responses are difficult to track, both in autochthonous tumor models and in patients, because antigens in spontaneous tumors are largely unknown or not sufficiently immunogenic. To circumvent this limitation, we generated a novel "patientlike" model of HCC, in which the adaptive T cell response can be studied. In particular, we aimed to characterize the adaptive T cell response in advanced au-

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“…Improved interaction ability and specificity of T cell can be used to kill tumor or cells infected by some virus more efficiently (93).…”

Section: Engineering Tcrmentioning

confidence: 99%

Manipulation of MHC-I/TCR Interaction for Immune Therapy

Liu

Gao

2008

Cell Mol Immunol

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Dual T Cell Receptor Expressing CD8+ T Cells with Tumor- and Self-Specificity Can Inhibit Tumor Growth without Causing Severe Autoimmunity

Cited by 25 publications

References 47 publications

Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma

Selective Depletion of Foxp3+ Regulatory T Cells Improves Effective Therapeutic Vaccination against Established Melanoma

Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation

Manipulation of MHC-I/TCR Interaction for Immune Therapy

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