TGF-β suppresses type 2 immunity to cancer

Liu, Ming; Kuo, Fengshen; Capistrano, Kristelle J.; Kang, Davina; Nixon, Briana G.; Wei, Shi; Chou, Chun; Mytrang, H.; Stamatiades, Efstathios G.; Gao, Shengyu; Li, Shun; Chen, Yingbei; Hsieh, James J.; Hakimi, A. Ari; Taniuchi, Ichiro; Chan, Timothy A.; Li, Ming O.

doi:10.1038/s41586-020-2836-1

Cited by 150 publications

(127 citation statements)

References 48 publications

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“…Conditional deletion of TgfbrII, specifically in CD4 + T cells, stops cancer progression via increased levels of IL-4 that are secreted by CD4 + Th2 cells. The IL-4 levels induce remodelling of the vasculature which subsequently results in hypoxia at avascular areas leading to cancer cell death [78]. Similar effects were observed after treatment with a bispecific antibody, 4T-Trap, targeting CD4 and TgfβrII [79].…”

Section: Immune Cells Within the Tumour Microenvironmentmentioning

confidence: 67%

“…In addition to the previously discussed impact of TGF-β on lymphocyte development and activity, it has recently been described that Tgf-β inhibits anti-cancer activity of CD4 + T cells in the TME of breast cancer in mice [78,79]. Conditional deletion of TgfbrII, specifically in CD4 + T cells, stops cancer progression via increased levels of IL-4 that are secreted by CD4 + Th2 cells.…”

Section: Immune Cells Within the Tumour Microenvironmentmentioning

confidence: 99%

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Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

2021

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Cancers may escape elimination by the host immune system by rewiring the tumour microenvironment towards an immune suppressive state. Transforming growth factor-β (TGF-β) is a secreted multifunctional cytokine that strongly regulates the activity of immune cells while, in parallel, can promote malignant features such as cancer cell invasion and migration, angiogenesis, and the emergence of cancer-associated fibroblasts. TGF-β is abundantly expressed in cancers and, most often, its abundance associated with poor clinical outcomes. Immunotherapeutic strategies, particularly T cell checkpoint blockade therapies, so far, only produce clinical benefit in a minority of cancer patients. The inhibition of TGF-β activity is a promising approach to increase the efficacy of T cell checkpoint blockade therapies. In this review, we briefly outline the immunoregulatory functions of TGF-β in physiological and malignant contexts. We then deliberate on how the therapeutic targeting of TGF-β may lead to a broadened applicability and success of state-of-the-art immunotherapies.

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Section: Immune Cells Within the Tumour Microenvironmentmentioning

confidence: 67%

Section: Immune Cells Within the Tumour Microenvironmentmentioning

confidence: 99%

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

2021

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“…However, it induces the conversion of naive T cells into T reg cells (previously known as suppressor T cells) that suppress the immune response. 180 A recent study showed that depletion of TβRII in 181 TGFβ can block the activation and maturation of cytotoxic CD8 + T cells by repressing the tumor antigen processing and presentation of DCs and inhibit CD8 + T cell proliferation through suppressing the expression of IFNγ and IL2. 172,[182][183][184] TGFβ promotes antigeninduced programmed cell death protein-1 (PD-1) expression in CD8 + T cells, which causes T cell exhaustion.…”

Section: Functions Of Tgfβ In the Tmementioning

confidence: 99%

Targeting TGFβ signal transduction for cancer therapy

Liu

Ren

Dijke

2021

Sig Transduct Target Ther

224

173

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Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial–mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.

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“…These include an increase in hypoxia-associated tumor cell death by remodeling the leaky tumor vasculature into a more organized structure. This study challenges existing notions of the pro-tumor roles of type 2 IL4-mediated CD4+ T cell responses and underscores the importance of further detailed mechanistic studies in the TNBC TIME [23].…”

Section: The Time and T Cellsmentioning

confidence: 59%

TIME Is a Great Healer—Targeting Myeloid Cells in the Tumor Immune Microenvironment to Improve Triple-Negative Breast Cancer Outcomes

Singh

Zhang

Rosen

2020

Cells

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The word myeloid is derived from the Greek word muelós which means “marrow”. Therefore, myeloid cells are described as cells that arise in the bone marrow. They can be distinguished from lymphoid cells based on their different differentiation trajectories—Lymphoid cells (B and T cells) are usually born in the bone marrow, but they need to migrate to lymphoid organs to mature and differentiate usually in response to antigens produced due to infections and diseases like cancer. On the other hand, myeloid cells do not follow this differentiation trajectory. They arise from the bone marrow, and do not need an encounter with antigens to gain their functionality. Thus, while lymphoid cells are a part of the adaptive immune system, myeloid cells are a part of the innate immune system. Hematopoiesis gives rise to two progenitor cells—the common myeloid progenitor (CMP) and the common lymphoid progenitor (CLP). The CMP can give rise to megakaryocytes, erythrocytes, mast cells and myeloblasts. Myeloblasts in turn lead to the formation of basophils, neutrophils, eosinophils and monocytes that can further differentiate into macrophages. This review will focus on macrophages as well as the phenotypes they acquire with the tumor immune microenvironment (TIME) in triple-negative breast cancer (TNBC). It will address how cancer cells in the tumor microenvironment (TME) recruit macrophages and may switch to recruiting neutrophils upon depletion of these tumor-associated macrophages (TAMs). Finally, it will also shed light on past and current treatment options that specifically target these cells and how those affect patient outcomes in TNBC.

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TGF-β suppresses type 2 immunity to cancer

Cited by 150 publications

References 48 publications

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

Targeting TGFβ signal transduction for cancer therapy

TIME Is a Great Healer—Targeting Myeloid Cells in the Tumor Immune Microenvironment to Improve Triple-Negative Breast Cancer Outcomes

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