Targeting TGF-β Signaling for Therapeutic Gain

Akhurst, Rosemary J.

doi:10.1101/cshperspect.a022301

Cited by 174 publications

(148 citation statements)

References 233 publications

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“…Conversely, inhibitory immunomodulatory cytokines such as TGF-β may be targeted in situ, specifically in the TME, to reduce their suppressive effects on NK cells. Once again, specific targeting of TGF-β in the TME is important due to potential toxicities associated with anti-TGF-β therapies administered systemically (290). Knudson et al reported an anti-PD-L1/TGFβ fusion protein (M7824), which depletes TGF-β signaling in the TME.…”

Section: Sensitizing Tumors For Nk Cell Killingmentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Section: Sensitizing Tumors For Nk Cell Killingmentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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“…Elevated TGF-β expression correlates with tumor progression and poorer prognosis. Thus,various inhibitors for TGF-β signaling, e.g., ligand trap using the extracellular domain of TβRII, neutralizing antibodies against TGF-βs or TβRII, and inhibitors for TβRI and/or TβRII kinases, have been developed, and some of them are in clinical trials [103,195].…”

Section: Extracellular Regulation Of Tgf-β Signalingmentioning

confidence: 99%

“…Since only some patients respond to the immune checkpoint therapies, an important strategy to improve their efficacies may be combination with other immune therapies. Inhibition of TGF-β signaling is potentially a very interesting way to treat cancers, and many preclinical and clinical trials are ongoing [195]. Thus, combination of the immune checkpoint therapy with inhibition of TGF-β signaling may be an attractive strategy to treat cancers, especially those resistant to current immune checkpoint inhibitors.…”

Section: Application Of Garp For Cancer Immunotherapymentioning

confidence: 99%

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

et al. 2018

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Transforming growth factor (TGF)-β regulates a wide variety of cellular responses, including cell growth arrest, apoptosis, cell differentiation, motility, invasion, extracellular matrix production, tissue fibrosis, angiogenesis, and immune function. Although tumor-suppressive roles of TGF-β have been extensively studied and well-characterized in many cancers, especially at early stages, accumulating evidence has revealed the critical roles of TGF-β as a pro-tumorigenic factor in various types of cancer. This review will focus on recent findings regarding epithelial-mesenchymal transition (EMT) induced by TGF-β, in relation to crosstalk with some other signaling pathways, and the roles of TGF-β in lung and pancreatic cancers, in which TGF-β has been shown to be involved in cancer progression. Recent findings also strongly suggested that targeting TGF-β signaling using specific inhibitors may be useful for the treatment of some cancers. TGF-β plays a pivotal role in the differentiation and function of regulatory T cells (Tregs). TGF-β is produced as latent high molecular weight complexes, and the latent TGF-β complex expressed on the surface of Tregs contains glycoprotein A repetitions predominant (GARP, also known as leucine-rich repeat containing 32 or LRRC32). Inhibition of the TGF-β activities through regulation of the latent TGF-β complex activation will be discussed.

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“…On the other hand, researchers have investigated the efficacy of the TGFβ pathway inhibition in preclinical and clinical trials using several TGFβ antagonists, including TGFβ antibodies, antisense oligonucleotides, and receptorkinase inhibitors. In cancer, this inhibition could attenuate the TGFβ-dependent EMT; however, due to the pleiotropic functions of TGFβ signaling -which regulates many normal physiological functions and various steps of cancer progression -the effects of TGFβ inhibitors in cancer therapy remain unpredictable (63). Furthermore, the progressive cascade of events in cancer metastasis is activated by TGFβ, which recruits several cell types in the tumor microenvironment -not just primary tumor cells but also stromal and immune cells (64).…”

Section: Perspectivesmentioning

confidence: 99%

Interplay of TGFβ signaling and microRNA in thyroid cell loss of differentiation and cancer progression

Fuziwara

Saito

Kimura

2019

Archives of Endocrinology and Metabolism

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Thyroid cancer has been rapidly increasing in prevalence among humans in last 2 decades and is the most prevalent endocrine malignancy. Overall, thyroid-cancer patients have good rates of long-term survival, but a small percentage present poor outcome. Thyroid cancer aggressiveness is essentially related with thyroid follicular cell loss of differentiation and metastasis. The discovery of oncogenes that drive thyroid cancer (such as RET, RAS, and BRAF), and are aligned in the MAPK/ERK pathway has led to a new perspective of thyroid oncogenesis. The uncovering of additional oncogenemodulated signaling pathways revealed an intricate and active signaling cross-talk. Among these, microRNAs, which are a class of small, noncoding RNAs, expanded this cross-talk by modulating several components of the oncogenic network-thus establishing a new layer of regulation. In this context, TGFβ signaling plays an important role in cancer as a dual factor: it can exert an antimitogenic effect in normal thyroid follicular cells, and promote epithelial-to-mesenchymal transition (EMT), cell migration, and invasion in cancer cells. In this review, we explore how microRNAs influence the loss of thyroid differentiation and the increase in aggressiveness of thyroid cancers by regulating the dual function of TGFβ. This review provides directions for future research to encourage the development of new strategies and molecular approaches that can improve the treatment of aggressive thyroid cancer.

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Targeting TGF-β Signaling for Therapeutic Gain

Cited by 174 publications

References 233 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Intracellular and extracellular TGF-β signaling in cancer: some recent topics

Interplay of TGFβ signaling and microRNA in thyroid cell loss of differentiation and cancer progression

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