TGFb-redirected immune cells: Novel opportunityfor treatment of castration resistant prostate cancer

Background: TGFb is a multifunctional cytokine that playsa double-faced role in the body. Although, normally TGFb isan inhibitor in early-stage cancer, it acts as a promoter in advancedcancers. In patients with castration resistant prostatecancer (CRPC), dysregulated TGF-β signaling leads to a highlyincrease of TGFb concentration in blood and the tumor microenvironment(TME), which excludes T/NK cells from theTME and serves as a master switch for immunosuppressionand inhibition of anti-tumor activity of T/NK cells and. Hence,these patients fail to respond to immune checkpoint blockades.Development of new therapeutic strategies with high specificityin the light of personalized medicine may overcome thisresistance. Here, we explain different strategies of redirectingTGFb-resistant T/NK cells as a novel opportunity for advancedprostate cancer immunotherapy.Materials and Methods: In this review, the data were extractedfrom google scholar papers from ۲۰۰۹ to ۲۰۲۳ and clinicaltrials data.Results: So far, several strategies have been used to specificallyinhibit/or invert the immunosuppression effects of TGFbon T and NK cells. Feasibility, safety and efficacy of thesetechniques have been proven in preclinical studies, suggestingthat they can promote the efficiency of immune cell therapyof advanced solid tumors including prostate cancer. Generally,these techniques are based on three approaches: First, insertionof a dominant negative TGFb receptor II (dnTGFbRII), a TGFbreceptor ۲ which lacks the signaling domains, in T/NK cells usingviral transduction or CRISPER/Cas۹ gene editing. Second,knocking out the TGFbRII in T/NK cells. Third, inverting theTGFb receptor cytosolic signaling in NK/T cells to a stimulatingsignal through the viral transduction or knocking in a chimericantigen receptor (CAR).Conclusion: Taken together, it was exhibited that the specificblocking of TGFb signaling, knocking out of TGFbRII, or invertinginhibitory signal of TGFb in T/NK cells can improvetheir tumor infiltration, cytotoxicity and survival. Recently,some of these super-immune cells have been translated to clinicaltrial.

کلیدواژه ها:

Tumor Growth Factor ، Immunotherapy ، Cancer ، Gene Editing ، Prostate Cancer