TRANSFORMING GROWTH FACTOR-β REGULATION OF IMMUNE RESPONSES

Li, Ming O.; Wan, Yisong Y.; Sanjabi, Shomyseh; Robertson, Anna Karin; Flavell, Richard A.

doi:10.1146/annurev.immunol.24.021605.090737

Cited by 1,998 publications

(1,833 citation statements)

References 372 publications

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“…TGF-β1 can regulate the development and function of all leukocytes, including T regulatory cells, dendritic cells (DC), NK cells and B cells [71]. Both the differentiation state of the cells and the presence of immunomodulatory molecules, including co-stimulatory molecules and cytokines, influence the effect of TGF-β1 on T cell function.…”

Section: Role Of Transforming Growth Factor-β In Til Hyporesponsivenessmentioning

confidence: 99%

“…High levels of TGF-β1 have also been associated with poor prognosis [76]. Since TGF-β1 is highly expressed in the tumor microenvironment and has been shown to suppress both the acquisition and expression of T cell effector function [77], it is likely that it may be at least partially responsible for the failure of TIL to control tumor progression [71].…”

Section: Role Of Transforming Growth Factor-β In Til Hyporesponsivenessmentioning

confidence: 99%

See 1 more Smart Citation

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.

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Section: Role Of Transforming Growth Factor-β In Til Hyporesponsivenessmentioning

confidence: 99%

Section: Role Of Transforming Growth Factor-β In Til Hyporesponsivenessmentioning

confidence: 99%

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Barnas

Simpson-Abelson

Yokota

et al. 2010

Cancer Microenvironment

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“…TGF-b is a well known pleiotropic cytokine that exerts immunosuppressive effects in many different ways, including the inhibition of T-cell proliferation and T-cell effector functions. 22,23 TGF-b also promotes the generation of Tregs, which results in added immunosuppression. 24 As high levels of TGF-b are produced by many types of tumors, the decorin-mediated suppression of TGF-b might contribute to the activation of an antitumor immune response, ultimately leading to better therapeutic effects in the lung metastasis model.…”

Section: Adenovirus Expressing Decorin I-k Choi Et Almentioning

confidence: 99%

Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy

et al. 2009

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The pressing challenge for contemporary gene therapy is to deliver enough therapeutic genes to enough cancer cells in vivo. With the aim of improving viral distribution and tumor penetration, we explored the use of decorin to enhance viral spreading and tumor tissue penetration. We generated decorin-expressing replication-incompetent (dl-LacZ-DCNG, dl-LacZ-DCNQ and dl-LacZ-DCNK) and replication-competent (Ad-DE1B-DCNG, Ad-DE1B-DCNQ and Ad-DE1B-DCNK) adenoviruses (Ads). Point mutants of decorin gene (DCNG), DCNK and DCNQ, have a negative and moderate binding affinity to type-I collagen fibril, respectively. In both tumor spheroids and established solid tumors in vivo, tissue penetration potency of dl-LacZ-DCNG was greatly enhanced than those of dl-LacZ, dl-LacZ-DCNQ and dl-LacZ-DCNK, and this enhanced tissue penetration effect derived from decorinexpressing Ad was dependent on the binding affinity of decorin to collagen fibril. Expression of DCNG enhanced viral spread of replicating Ad, leading to improved tumor reduction and survival benefit. Moreover, the tumoricidal effects of Ad-DE1B-DCNQ and Ad-DE1B-DCNK were lessened, as the binding affinity to collagen was decreased, showing that the increased cancer cell cytotoxicity was driven by the action of decorin on extracellular matrix (ECM). Furthermore, Ad-DE1B-DCNG substantially decreased ECM components within the tumor tissue. Finally, intratumoral injection of Ad-DE1B-DCNG in primary tumor site greatly reduced the formation of B16BL6 melanoma cell pulmonary metastases in mice. Taken together, these data show the utility of decorin as a dispersion agent and highlight its utility and potential in improving the efficacy of replicating Ad-mediated cancer gene therapy.

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“…6E and F). TGF-b1 and TGF-b2 have pleiotropic functions (for review see [46]) and have been described to be expressed very strongly by glioma cells [5][6][7]. The importance of TGF-b in supporting glioma growth is attested by experiments blocking TGF-b production, which positively influence the survival of rats with established gliomas [47].…”

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confidence: 99%

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

et al. 2009

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Gliomas localized within the CNS are generally not rejected by the immune system despite being immunogenic. This failure of the immune system has been associated both with glioma-derived immunosuppressive molecules and the immune-privileged state of the CNS. However, the relative contribution of tumor location to the glioma-mediated immunosuppression, as well as the immune mechanisms involved in the failure of glioma rejection are not fully defined. We report here that syngeneic GL261 gliomas growing either intracranially or subcutaneously in mice are infiltrated by DC and T cells. However, only subcutaneous gliomas elicit an effective anti-tumor immune response. In contrast to DC infiltrating subcutaneously grown GL261 gliomas, tumor-infiltrating DC from intracranial gliomas do not activate antigen-dependent T-cell proliferation in vitro. In addition, brain-localized GL261 gliomas are characterized by significantly higher numbers of Foxp3 1 Treg and higher levels of TGF-b1 mRNA and protein expression when compared with GL261 gliomas in the skin. Our data show that gliomas in the CNS, but not in the skin, give rise to TGF-b production and accumulation of both Treg and functionally impaired DC. Thus, not the tumor itself, but its location dictates the efficiency of the antitumor immune response.Key words: DC . Immune privilege . Treg . Tumor immunity Supporting Information available online IntroductionMalignant gliomas, especially the most frequent and aggressive form known as glioblastoma multiforme, are among the most fatal types of tumors. The best standard of care for glioblastoma multiforme, consisting of surgery followed by radiotherapy and chemotherapy with temozolomide, is associated with a median overall survival of 14.6 months following diagnosis [1]. Gliomas have been shown to result in reduced peripheral T-cell responses [2], down-modulated function of circulating APC [3] and particularly to suppressed maturation of peripheral DC [4]. In addition, the localization of the glioma within the immune-privileged CNS, combined with the production of tumorderived immunosuppressive molecules including , , VEGF [9] and prostaglandins [10], is suggested to account for the absence of a successful anti-tumor immune Ã These authors contributed equally to this work. response. As a consequence, glioma patients fail to generate an effective immune response against the intracranially growing tumors. Although it occurs rarely, gliomas are able to metastasize to locations outside of the brain [11]. The low frequency of peripheral glioma metastases might be due to an efficient recognition of tumor cells outside of the CNS. Gliomas express tumor-associated antigens such as ER-2, gp100, and MAGE-1, which can be recognized by cytotoxic T lymphocyte clones [12]. Furthermore, T-cell clonal expansion has been detected in glioma patients [13] and vaccination of patients with autologous tumor lysate-pulsed DC or autologous tumor peptide-pulsed DC [14] can elicit tumor-specific T-cell responses and infiltration of cytotoxic and me...

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TRANSFORMING GROWTH FACTOR-β REGULATION OF IMMUNE RESPONSES

Cited by 1,998 publications

References 372 publications

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg

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TRANSFORMING GROWTH FACTOR-β REGULATION OF IMMUNE RESPONSES

Cited by 1,998 publications

References 372 publications

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy

Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3+ Treg

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Resources

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Site‐specific anti‐tumor immunity: Differences in DC function, TGF‐β production and numbers of intratumoral Foxp3⁺ Treg