Controlling a Tumor Microenvironment

Transforming growth factor-beta (TGF-β) is a dynamic cytokine that is part of the transforming growth factor superfamily.

The TGF-β signaling pathway is connected to numerous cellular processes in both the developing embryo and the adult organism, including cell growth, cell differentiation, cellular homeostasis, apoptosis and other cellular functions.

TGF-β signaling in cancer is a complicated process. While TGF-β can facilitate the suppression of tumor formation, conversely, it can also foster it.

In healthy cells and early-stage cancers, TGF-β signaling suppresses tumor formation by impeding cell growth and apoptosis. However, in progressive cancers, TGF-β signaling receives a variety of tumor-promoting effects through specific adaptation or signaling pathways bypass.

There are two mechanisms to explain the tumor-promoting effects of TGF-Β:

1. The tumor utilizes TGF-β to encourage the epithelial mesenchymal transition (EMT), thereby amplifying the migration, infiltration, invasion and extravasation of the tumor cells.

2. Through paracrine signaling, TGF-β can assist in the formation of the tumor microenvironment (TME), switching on cancer-associated fibroblasts (CAF), encourage angiogenesis, generate extracellular matrix (ECM), impede anti-tumor immune response and ultimately foster tumor metastasis (Figure 1).

Tumor-promoting and suppressing effect of TGF-β.

Figure 1. Tumor-promoting and suppressing effect of TGF-β. Image Credit: ACROBiosystems

The TME is the environment surrounding a tumor, including the bordering blood vessels, fibroblasts, immune cells, signaling molecules and ECM. TEM is crucial for tumor immune escape. It generates a barrier to shield the tumor from the immune system and eventually leads to tumor metastasis.

Therefore, TME is vital for the development of a tumor and is one of the principal issues that need to be addressed in tumor clinical treatment.

The TEM is induced by TGF-β through the following steps:

1. TGF-β activates/differentiates fibroblasts, mesenchymal stem cells, epithelial tumor cells, adipose tissue-derived stem cells and endothelial cells (Figure 2A). The fibroblasts are critical elements of the TME.

They encourage immune escape and angiogenesis by dispensing ECM and cytokines. Endothelium cells are situated on the surface of blood and lymphatic vessels. Blood vessels feed tumors by supplying blood/oxygen/nutrients, eliminating waste and limiting the entry and exit of immune cells and other substances.

TGF-β acts directly and indirectly on endothelial cells to foster angiogenesis and migration in TME (Figure 2b).

2. TGF-β represses the immune system by limiting the function of the immune cell populations in the tumor microenvironment (TME), which is spotted with a diverse range of innate and adaptive immune cells.

  • TGF-β subdues tumor adaptive immunity by principally impeding T cell activation, differentiation, proliferation and migration (Fig. 2C). TGF-β typically inhibits the differentiation of primary CD4 + T cells into various effector subtypes, but it can prompt the transfiguration of primary T cells into regulatory T cells, which have an active immunosuppressive role.

  • TGF-β prevents the activation and maturation of cytotoxic CD8 + T cells by impeding the conversion of tumor antigens and the expression of DCs. TGF-β also limits the proliferation of CD8 + T cells by preventing the expression of IFNγ and IL2.

  • In addition, TGF-β encourages the expression of antigen-induced programmed cell death protein 1 (PD-1) in CD8 + T cells, which results in T cell failure.

The function of TGF-β in TEM.

Figure 2. The function of TGF-β in TEM. Image Credit: ACROBiosystems

Since TGF-β is implicated in numerous aspects of tumor genesis and development, the suppression of TGF-β signal transduction produces many research targets for anti-tumor therapy, which has become a rapidly developing research field of new anti-cancer therapies.

Cancer cells often break free from TGF-β-induced cell suppression responses, which is why, in many cases, cancer patients show recurrent symptoms subsequent to chemotherapy, targeted therapy, or radiation.

The response of a single treatment regimen is restricted. Yet, the development of combination therapy has become widely accepted.

Utilizing an anti- TGF-β drug in parallel with one of the following treatments, including immune checkpoint inhibitors (such as PD-1/PD-L1 antibodies), radiation therapy, cytotoxic drugs and cancer vaccines.

In accordance with the clinical data, the anti-tumor effect of the combination of PD-L1 antibody and TGF-β antibody is more efficient than that of single-drug treatment (Table 1). Yet, the anti-cancer mechanism of TGF-β inhibitors is still not fully understood.

Table 1. The combination of PD-L1 and TNF- β antibodies in clinical trials. Source: ACROBiosystems

Drug name   The highest R&D status worldwide Active
company
Active Indications target Mechanism
PM-8001 phase II
clinical trials
Pumis Biotechnology
(Zhuhai)Co., Ltd.
solid
tumor
PD-L1
TGF-β
Programmed death-ligand 1 inhibitors (PD-L 1 Inhibitor); Transforming growth factor beta inhibitors (TGF-β Inhibitor)
HBM-7015 Preclinical development Harbour BioMed solid
tumor
TGF-β1
PD-L1
Transforming growth factor beta 1 inhibitors (TGF-β 1 Inhibitor); Programmed death-ligand 1 inhibitors (PD-L1 Inhibitor)

 

Further developing the understanding of the interaction between the human body and TGF-β signaling is the crucial element to improving clinical efficacy in the future.

TGF-β signal transduction has garnered significant attention in scientific and clinical studies due to its key role in tumor immune escape. A comprehensive understanding of the mechanism of TGF-β can help enhance the tumor treatment plans in clinical practice and offer a new direction of cancer drug development across the industry.

ACROBiosystems developed a series of TGF-beta 1, Latent TGF-beta 1, TGF-beta 3, TGF-beta RII proteins independently and their biological activity has been validated by numerous technologies, including Cell-based assay and ELISA with excellent feedback from customers.

The relevant protocol is supplied for free in order to shorten the R&D cycle.

Product list

Table 2. Source: ACROBiosystems

Molecule Cat. No. Product Description
TGF-beta 1 TG1-H4212 ActiveMax® Human TGF-Beta 1 / TGFB1 Protein, Tag Free

TG1-H8217

Biotinylated Human TGF-Beta 1 / TGFB1 Protein, Avitag™

TG1-M5218

Mouse TGF-Beta 1 / TGFB1 Protein
TGF-beta RII TG2-H5252 Human TGF-beta RII / TGFBR2 Protein, Fc Tag

TG2-H82E4

Biotinylated Human TGF-beta RII / TGFBR2 Protein, His, Avitag™

TG2-H82F6

Biotinylated Human TGF-beta RII / TGFBR2 Protein, Fc, Avitag™ (MALS verified)

TG2-H52H5

Human TGF-beta RII / TGFBR2 Protein, His Tag (MALS verified)

TG2-M82H5

Biotinylated Mouse TGF-beta RII / TGFBR2 Protein, His, Avitag™
LAP
(TGF-beta 1)
LAP-H5245 Human LAP (TGF-beta 1) Protein, His Tag

LAP-H82Q6

Biotinylated Human LAP (TGF-beta 1) Protein, His, Avitag™
Latent TGF-beta 1 TG1-H524x Human Latent TGF-beta 1 / TGFB1 Protein, His Tag

TG1-H82Qb

Biotinylated Human LAP (TGF-beta 1) Protein, His, Avitag™

TG1-C5243

Cynomolgus Latent TGF-beta 1 (C33S) Protein, His Tag
TGF-beta 3 TG3-H8218 Biotinylated Human Latent TGF-beta 3 / Latent TGFB3 Protein, Avitag™

 

Assay data

Immobilized ActiveMax® Human TGFB1, Tag Free (Cat. No. TG1-H4212) at 2 μg/mL (100 μL/well) can bind Human TGFBR2, Fc Tag (Cat. No. TG2-H5252) with a linear range of 0.3-5 ng/mL (QC tested).

Immobilized ActiveMax® Human TGFB1, Tag Free (Cat. No. TG1-H4212) at 2 μg/mL (100 μL/well) can bind Human TGFBR2, Fc Tag (Cat. No. TG2-H5252) with a linear range of 0.3-5 ng/mL (QC tested). Image Credit: ACROBiosystems

Immobilized Human LAP (TGF-beta 1), His Tag (Cat. No. LAP-H5245) at 2 μg/mL (100 μL/well) can bind Biotinylated Human ITGAV&ITGB6 Heterodimer Protein, His,Avitag&Tag Free (Cat. No. IT6-H82E4) with a linear range of 0.8-25 ng/mL (QC tested).

Immobilized Human LAP (TGF-beta 1), His Tag (Cat. No. LAP-H5245) at 2 μg/mL (100 μL/well) can bind Biotinylated Human ITGAV&ITGB6 Heterodimer Protein, His,Avitag&Tag Free (Cat. No. IT6-H82E4) with a linear range of 0.8-25 ng/mL (QC tested). Image Credit: ACROBiosystems

Cell based assay

ActiveMax® Human TGFB1, Tag Free (Cat. No. TG1-H4212) inhibits the IL-4-dependent proliferation of TF-1 cells. The ED50 for this effect is 0.43-0.91 ng/mL (Routinely tested).

ActiveMax® Human TGFB1, Tag Free (Cat. No. TG1-H4212) inhibits the IL-4-dependent proliferation of TF-1 cells. The ED50 for this effect is 0.43-0.91 ng/mL (Routinely tested). Image Credit: ACROBiosystems

About ACROBiosystems

ACROBiosystems is a leading manufacturer of recombinant proteins and other critical reagents to support the development of target therapeutics. The company employs an application-oriented development strategy, with a particular focus on product design, quality control, and solution-based support. Our products and services enable anyone in the field of drug development to have a more intuitive and streamlined process.

To respond to the coronavirus pandemic, ACROBiosystems has developed SARS-CoV-2 antigens specifically designed and optimized for serological test kits, including Spike-derived antigen S1, RBD, and Nucleocapsid protein. Proteins have been supplied to diagnostic companies in large quantities.


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Last updated: Apr 15, 2021 at 4:15 AM

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