TGF-β Immune Checkpoint Molecule for Drug Development
Transforming growth factor (TGF)-β is one of the essential regulatory cytokines produced by several immune cells. Most of this cytokine family exist in variant forms (e.g., TGFβ1, β2, and β3) with high homology. The TGF-β signaling pathway has pleiotropic functions in regulating cell growth, differentiation, apoptosis, motility and invasion, angiogenesis, immune response, and immune tolerance.
Fig.1 The role of TGF-β in cancer. (Massagué, 2008)
TGF-β as Inhibitory Molecule
TGF-β plays a pleiotropic role in tumor biology, promoting tumor proliferation, invasion, metastasis, and escape from immune surveillance. TGF-β signaling pathway exerts tumor-suppressive effects to control early-stage tumors by promoting cell cycle arrest and apoptosis; however, in advanced stages, it allows for suppressing the immune system by inducing Tregs and suppressing cytotoxic T cells and promotes cancer cell proliferation, invasion, and metastases. It is undisputed that the TGF-β signaling pathway plays a critical role in generating a favorable microenvironment for tumor initiation, development, and metastasis throughout all carcinogenesis steps. Thus, blockade of the TGF-β has become an emerging strategy to enhance immunotherapy across several cancer types. This also allows for potential combination with other therapies such as immune checkpoint inhibitors and chemotherapies.
Fig.2 TGF-β inhibition promotes T cell infiltration. (Gupta, 2019)
Clinical Development of Drugs Targeting TGF-β
Due to its significant and varied roles in promoting tumor growth and metastasis, TGF-β has been identified as a therapeutic target in cancer treatment. Three methods can achieve the TGF-β signaling blockade: blocking the ligand, disrupting the ligand-receptor interaction, or inhibiting the receptor tyrosine kinase activity. Some clinical studies have demonstrated that targeting TGF-β signaling could help treat many tumors, particularly in combination with other forms of cancer therapies (such as radiation, chemotherapy, immune checkpoint targeting, and tumor vaccines). Currently, many different inhibitors targeting TGF-β are undergoing clinical development. The future of TGF-β inhibitors in cancer therapy is promising and opens new challenges in terms of biomarkers and patient selection.
Services at Creative Biolabs
Creative Biolabs is a well-recognized expert who supports a broad range of drug development projects for immune checkpoints. Currently, a series of custom services for immune checkpoint TGF-β is available at Creative Biolabs, including but not limited to: