Transforming Growth Factor-β: A Multifunctional Regulator of Cancer Immunity

Abstract

Transforming growth factor-β (TGF-β) was originally identified as an anti-tumour cytokine. However, there is increasing evidence that it has important roles in the tumour microenvironment (TME) in facilitating cancer progression. TGF-β actively shapes the TME via modulating the host immunity. These actions are highly cell-type specific and complicated, involving both canonical and non-canonical pathways. In this review, we systemically update how TGF-β signalling acts as a checkpoint regulator for cancer immunomodulation. A better appreciation of the underlying pathogenic mechanisms at the molecular level can lead to the discovery of novel and more effective therapeutic strategies for cancer.

TGF-β Signaling: From Tissue Fibrosis to Tumor Microenvironment

“…[ 32 , 140 , 141 , 149 , 150 , 151 ]. Nevertheless, their potential functions in the TME with TGF-β pathway activation is still largely unclear and is starting to be recognized [ 12 , 152 , 153 ]. Therefore, better understanding of TGF-β downstream signaling would uncover precise therapeutic targets from the fibrotic microenvironment for cancer.…”

AANG: A natural compound formula for overcoming multidrug resistance via synergistic rebalancing the TGF‐β/Smad signalling in hepatocellular carcinoma

“…1,2 Recently, we discovered the essentialness of Smad3 in the microenvironment for developing inflammatory diseases including cancer. 1,5,13,21 Smad3 deficiency protected mice against tumour growth, invasion and metastasis, where a markedly reduction in angiogenesis (CD31, VEGF), invasion and metastasis (MMPs), and immunosuppression (decrease in Foxp3 + Treg but increase in NKp46 + NK cells)…”

Transforming growth factor‐beta1 and myeloid‐derived suppressor cells: A cancerous partnership

“…TGF-β1 is a secreted cytokine involved in a plethora of distinct biological processes in tumor progression, including cell growth and proliferation, differentiation and development, apoptosis, angiogenesis, and immune response suppression, and metastasis. 2,4,6 Three TGF-β types have been described so far in mammalians TGF-β1, -β2, and -β3 with a high level of sequence homology but with different expression modes and different functions. 15 TGF-β1, also named TGF-β, is the one that has crucial roles in tumor progression and development of a protumorigenic microenvironment.…”

“…15 TGF-β1, also named TGF-β, is the one that has crucial roles in tumor progression and development of a protumorigenic microenvironment. 4,6 Although lacking the classic TATA boxes, the TGF-β1 gene possesses multiple regulatory cis-elements susceptible to activation by several immediate early genes and oncogenes or inhibition by tumor suppressors. 16 TGF-β1 is synthesized as a 75 kDa precursor, that is, cleavage by furin-type convertase to form a small latent complex (SLC) that contains the latency-associated peptide (LAP) and TGF-β1.…”

“…2,31 The critical roles of TGF-β1 as a tumor promoter include pro-metastatic cancer and stromal cell responses, EMT induction, and the development of immune-suppressive TME. 2,4,6,32 Part of the molecular armament for tumor suppressor TGF-β1 activity is the capacity to potently inhibit epithelial cell proliferation due to its ability to regulate cyclindependent kinase (CDK) inhibitors. This cytokine induces p15 Ink4b and p21 Cip1 expression to inhibit cyclinD-CDK4/6 and cyclinE/A-CDK2 complexes p16 ink4a and p19 ARF expression that results in retaining the tumor-suppressor retinoblastoma (Rb) protein in a hyperphosphorylated state.…”