7.1.8　TGF-β

TGF-β plays a dual role in the tumorigenic process.During the initial stages of tumorigenesis,TGF-β inhibits tumor development due to cell-cycle blockade in cells undergoing transformation.However, tumor cells develop resistance mechanisms to the anti-proliferative activity of TGF-β,and in later stages of tumor development, TGF-β acts both on tumor cells and on cells of the TME to promote tumor progression.In tumor cells, TGF-β is a key mediator of the epithelialmesenchymal transition.In the tumor stromal compartments, this cytokine promotes the release of angiogenic factors, such as VEGF, and the recruitment of Treg cells and myeloid cells with a pro-tumor polarization, such as neutrophils, macrophages, myeloid-derived suppressor cells(MDSCs) and tolerogenic DCs.Moreover, TGF-β decreases the activity of NK cells and CD8+T lymphocytes [2,4].(https://www.daowen.com)

The relevance of the immunosuppressive activity of this cytokine in tumors has been conducive to the development of several small molecules, peptides, antisense oligonucleotides, cytokine traps and antibodies to block the TGF-β pathway in cancer.Although their efficacy as monotherapy agents has been disappointing, their activity in combination with anti-PD-1 or antiPD-L1 agents has renewed interest in inhibitors tackling the functions of this cytokine.TGF-β might be the main driver of immune cell exclusion in several tumors.Numerous clinical trials are testing the safety and anti-tumor activity of the combined blockade of TGF-β using small molecules, such as galunisertib, or antagonistic monoclonal antibodies, such as fresolimumab, with PD-1-PD-L1 such as nivolumab or durvalumab (NCT02423343 and NCT02734160).Additionally, M7824, a compound designed to simultaneously block both targets, is undergoing clinical testing(NCT03451773 and NCT03451773).This construct combines a chimeric version of an anti-PD-L1 monoclonal antibody (avelumab) with a fragment of TGF-βR4 to entrap active TGF-β.Inhibiting this cytokine could be especially relevant in tumors treated with radiotherapy, as radiotherapy activates the latent form of TGF-β and induces its transcription [2, 5].