scholarly journals Targeting Transforming Growth Factor β to Enhance Cancer Immunotherapy

2006 ◽  
Vol 13 (4) ◽  
pp. 141-143 ◽  
Author(s):  
T. Hahn ◽  
Emmanuel Akporiaye
Keyword(s):  
Immune System ◽  
Growth Factor ◽  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Human Tumours

Human tumours have evolved intricate mechanisms to evade the immune system, either by avoiding recognition or by inhibiting and eliminating immune cells. [...]

scholarly journals Transforming Growth Factor-β: An Agent of Change in the Tumor Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Christina H. Stuelten ◽  
Ying E. Zhang
Keyword(s):  
Growth Factor ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Potent Inhibitor ◽  
Early Stage ◽  
Transforming Growth Factor Β ◽  
Metabolic Reprogramming ◽  
Adult Tissue ◽  
Core Property ◽  
Agent Of Change

Transforming Growth Factor-β (TGF-β) is a key regulator of embryonic development, adult tissue homeostasis, and lesion repair. In tumors, TGF-β is a potent inhibitor of early stage tumorigenesis and promotes late stage tumor progression and metastasis. Here, we review the roles of TGF-β as well as components of its signaling pathways in tumorigenesis. We will discuss how a core property of TGF-β, namely its ability to change cell differentiation, leads to the transition of epithelial cells, endothelial cells and fibroblasts to a myofibroblastoid phenotype, changes differentiation and polarization of immune cells, and induces metabolic reprogramming of cells, all of which contribute to the progression of epithelial tumors.

scholarly journals Transforming Growth Factor-β Signaling in Fibrotic Diseases and Cancer-Associated Fibroblasts

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1666
Author(s):  
Xueke Shi ◽  
Christian D. Young ◽  
Hongmei Zhou ◽  
Xiao-Jing Wang
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Cancer Associated Fibroblasts ◽  
The Matrix ◽  
Fibrotic Diseases ◽  
Fibrotic Disorders

Transforming growth factor-β (TGF-β) signaling is essential in embryo development and maintaining normal homeostasis. Extensive evidence shows that TGF-β activation acts on several cell types, including epithelial cells, fibroblasts, and immune cells, to form a pro-fibrotic environment, ultimately leading to fibrotic diseases. TGF-β is stored in the matrix in a latent form; once activated, it promotes a fibroblast to myofibroblast transition and regulates extracellular matrix (ECM) formation and remodeling in fibrosis. TGF-β signaling can also promote cancer progression through its effects on the tumor microenvironment. In cancer, TGF-β contributes to the generation of cancer-associated fibroblasts (CAFs) that have different molecular and cellular properties from activated or fibrotic fibroblasts. CAFs promote tumor progression and chronic tumor fibrosis via TGF-β signaling. Fibrosis and CAF-mediated cancer progression share several common traits and are closely related. In this review, we consider how TGF-β promotes fibrosis and CAF-mediated cancer progression. We also discuss recent evidence suggesting TGF-β inhibition as a defense against fibrotic disorders or CAF-mediated cancer progression to highlight the potential implications of TGF-β-targeted therapies for fibrosis and cancer.

scholarly journals Transforming Growth Factor β Subverts the Immune System into Directly Promoting Tumor Growth through Interleukin-17

2008 ◽  
Vol 68 (10) ◽  
pp. 3915-3923 ◽  
Author(s):  
Jeong-Seok Nam ◽  
Masaki Terabe ◽  
Mi-Jin Kang ◽  
Helen Chae ◽  
Nga Voong ◽  
...  
Keyword(s):  
Immune System ◽  
Growth Factor ◽  
Tumor Growth ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 17

A GMCSF & IL15 Fusokine Leads to Paradoxical Immunosuppression In Vivo Via Asymmetrical JAK/STAT Signalling through the IL15 Receptor Complex.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3187-3187
Author(s):  
Moutih Rafei ◽  
Jian Hui Wu ◽  
Borhane Annabi ◽  
Laurence Lejeune ◽  
Moira Francois ◽  
...  
Keyword(s):  
Immune System ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
De Novo ◽  
Adaptive Immune System ◽  
Transforming Growth Factor Β ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Matrix Metalloproteinase 2 ◽  
Mouse Splenocytes

Abstract Immune stimulatory cytokines can be exploited to treat human ailments including cancer. Amongst cytokines identified for such use, granulocyte-macrophage colony stimulating factor (GMCSF) has been under much scrutiny since it acts directly on the adaptive immune system by enhancing antigen presentation as well as costimulation. Furthermore, interleukin (IL)15 possesses overlapping activities with IL2 such as the activation of T-cells and the stimulation of natural killing as well as additive stimulatory effects on the immune system distinct from IL2. These features make IL15 an attractive companion to GMCSF as part of an immunotherapeutic fusokine. Therefore, we hypothesized that a GMCSF and IL15 fusion protein (GIFT15) would possess greater immune stimulatory properties than their combined use. Unexpectedly, tumor cells engineered to secrete GIFT15 protein led to enhanced tumor growth and suppression of natural killer (NK) and NKT-cell recruitment in vivo, suggesting an unheralded immune suppressive effect. We found that GIFT15 has pleiotropic effects on an array of immune competent cells. More specifically, peritoneal macrophages treatment with GIFT15 secrete de novo the tissue inhibitor of metalloproteinase-2 (TIMP-2); activated matrix metalloproteinase-2 (MMP-2); transforming growth factor-β (TGF-β) as well as vascular endothelial growth factor (VEGF). In terms of ligand-receptor interactions, we show by BIAcore analysis that the GIFT15 fusokine has increased affinity for the αchain component of the trimeric IL15R, which contributes to aberrant signalling through the β chain manifested by the hyperphosphorylation of STAT3 both in macrophages and splenocytes. In addition, GIFT15 and IL15R virtual interaction studies suggests that the GMCSF domain component of the GIFT15 fusokine may hinder the interaction of the IL15 domain component with the IL15Rγ chain, and thus leading to a downregulation of the JAK3/STAT5 pathway. We also show that GIFT15 leads to suppression of common γ chain-mediated STAT5 phosphorylation and blockade of the IL15-dependent IFN-γ response in mouse splenocytes We tested the utlity of GIFT15 as an immunosuppressor directly in vivo and demonstrated that it allowed engraftment of allogeneic B16F0 and human xenograft U87MG glioma cells in immunocompetent mice in a CD4-dependent maner. Thus, GIFT15 defines a new class of fusokine which mediates pro-angiogenic and potent immunosuppressive effects via aberrant signalling by the IL15R in lymphomyeloid cells. We propose that GIFT15 may serve as a novel pharmaceutical for tolerance induction of somatic allo or xenografts in mammals without requirement of toxic conditioning regimens.

scholarly journals Role of Transforming Growth Factor-β1 in Regulating Fetal-Maternal Immune Tolerance in Normal and Pathological Pregnancy

2021 ◽  
Vol 12 ◽  
Author(s):  
Dongyong Yang ◽  
Fangfang Dai ◽  
Mengqin Yuan ◽  
Yajing Zheng ◽  
Shiyi Liu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Immune Tolerance ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Transforming Growth Factor Β ◽  
Normal Pregnancy ◽  
Cell Functions ◽  
Tgf Β1

Transforming growth factor-β (TGF-β) is composed of three isoforms, TGF-β1, TGF-β2, and TGF-β3. TGF-β1 is a cytokine with multiple biological functions that has been studied extensively. It plays an important role in regulating the differentiation of immune cells and maintaining immune cell functions and immune homeostasis. Pregnancy is a carefully regulated process. Controlled invasion of trophoblasts, precise coordination of immune cells and cytokines, and crosstalk between trophoblasts and immune cells play vital roles in the establishment and maintenance of normal pregnancy. In this systematic review, we summarize the role of TGF-β1 in regulating fetal-maternal immune tolerance in healthy and pathological pregnancies. During healthy pregnancy, TGF-β1 induces the production of regulatory T cells (Tregs), maintains the immunosuppressive function of Tregs, mediates the balance of M1/M2 macrophages, and regulates the function of NK cells, thus participating in maintaining fetal-maternal immune tolerance. In addition, some studies have shown that TGF-β1 is dysregulated in patients with recurrent spontaneous abortion or preeclampsia. TGF-β1 may play a role in the occurrence and development of these diseases and may be a potential target for the treatment of these diseases.

Breast-feeding regulates immune system development via transforming growth factor-β in mice pups

2018 ◽  
Vol 60 (3) ◽  
pp. 224-231 ◽  
Author(s):  
Keita Sakaguchi ◽  
Akemi Koyanagi ◽  
Fumitaka Kamachi ◽  
Akiko Harauma ◽  
Asako Chiba ◽  
...  
Keyword(s):  
Immune System ◽  
Growth Factor ◽  
Breast Feeding ◽  
Transforming Growth Factor ◽  
System Development ◽  
Transforming Growth Factor Β ◽  
Immune System Development

scholarly journals Targeted Disruption of Smad3 Reveals an Essential Role in Transforming Growth Factor β-Mediated Signal Transduction

1999 ◽  
Vol 19 (4) ◽  
pp. 2495-2504 ◽  
Author(s):  
Michael B. Datto ◽  
Joshua P. Frederick ◽  
Lihua Pan ◽  
Anita J. Borton ◽  
Yuan Zhuang ◽  
...  
Keyword(s):  
Immune System ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Dermal Fibroblasts ◽  
Null Mouse ◽  
Developmental Defect ◽  
Plasminogen Activator Inhibitor 1 ◽  
Targeted Disruption

ABSTRACT The Smads are a family of nine related proteins which function as signaling intermediates for the transforming growth factor β (TGF-β) superfamily of ligands. To discern the in vivo functions of one of these Smads, Smad3, we generated mice harboring a targeted disruption of this gene. Smad3 null mice, although smaller than wild-type littermates, are viable, survive to adulthood, and exhibit an early phenotype of forelimb malformation. To study the cellular functions of Smad3, we generated Smad3 null mouse embryonic fibroblasts (MEFs) and dermal fibroblasts. We demonstrate that null MEFs have lost the ability to form Smad-containing DNA binding complexes and are unable to induce transcription from the TGF-β-responsive promoter construct, p3TP-lux. Using the primary dermal fibroblasts, we also demonstrate that Smad3 is integral for induction of endogenous plasminogen activator inhibitor 1. We subsequently demonstrate that Smad3 null MEFs are partially resistant to TGF-β’s antiproliferative effect, thus firmly establishing a role for Smad3 in TGF-β-mediated growth inhibition. We next examined cells in which Smad3 is most highly expressed, specifically cells of immune origin. Although no specific developmental defect was detected in the immune system of the Smad3 null mice, a functional defect was observed in the ability of TGF-β to inhibit the proliferation of splenocytes activated by specific stimuli. In addition, primary splenocytes display defects in TGF-β-mediated repression of cytokine production. These data, taken together, establish a role for Smad3 in mediating the antiproliferative effects of TGF-β and implicate Smad3 as a potential effector for TGF-β in modulating immune system function.

scholarly journals A máj és az immunrendszer

2015 ◽  
Vol 156 (30) ◽  
pp. 1203-1213 ◽  
Author(s):  
Lajos Jakab
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Growth Factor ◽  
B Lymphocytes ◽  
Acute Phase ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Acute Phase Reaction ◽  
Specific Immune Response ◽  
Phase Reaction

The liver is known to be the metabolic centre of the organism and is under the control of the central nervous system. It has a peculiar tissue structure and its anatomic localisation defines it as part of the immune system having an individual role in the defence of the organism. The determinant of its particular tissue build-up is the sinusoid system. In addition to hepatocytes, one cell row “endothelium”, stellate cells close to the external surface, Kupffer cells tightly to its inner surface, as well as dendritic cells and other cell types (T and B lymphocytes, natural killer and natural killer T-cells, mast cells, granulocytes) are present. The multitudes and variety of cells make it possible to carry out the tasks according to the assignment of the organism. The liver is a member of the immune system having immune cells largely in an activated state. Its principal tasks are the assurance of the peripheral immune tolerance of the organism with the help of the haemopoetic cells and transforming growth factor-β. The liver takes part in the determination of the manner of the non-specific immune response of the organism. In addition to acute phase reaction of the organism, the liver has a role in the adaptive/specific immune response. These functions include retardation of the T and B lymphocytes and the defence against harmful pathogens. With the collaboration of transforming growth factor-β, immunoglobulins and their subclasses are inhibited just as the response of the T lymphocytes. The only exception is the undisturbed immunoglobulin A production. Particularly important is the intensive participation of the liver in the acute phase reaction of the organism, which is organised and guided by the coordinated functions of the cortico-hypothalamo-hypophysis-adrenal axis. Beside cellular elements, hormones, adhesion molecules, chemokines and cytokines are also involved in the cooperation with the organs. Acute phase reactants play a central role in these processes. Until recently the α2-macroglobulin was not considered as an acute reactant of the organism, but it is now functionally included in the acute phase reaction presumably due to its close connection with the transforming growth factor-β. Transforming growth factor-β has extraordinarily important roles in all phases of inflammation and in the specific immune response. The peripheral immune tolerance of the organism involves tightly coupled regulation of proliferation, differentiation and survival of lymphocytes. Orv. Hetil., 2015, 156(30), 1203–1213.

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