Transforming growth factor-beta receptor type 2 (TGFBR2) signaling complex on engineered T cells (TGFBR2 signaling complex)

The Transforming growth factor-beta receptor type 2 (TGFBR2) signaling complex on engineered T cells is a synthetic therapeutic target designed to overcome the potent immunosuppressive effects of the tumor microenvironment (TME). In many solid tumors, high levels of TGF-beta act as a major inhibitor of T cell function, promoting exhaustion and limiting the efficacy of adoptive cell therapies (UniProt P37173). By engineering T cells to express a dominant-negative TGFBR2 (dnTGFBRII), which lacks the intracellular signaling domain, or a chimeric switch receptor that fuses the TGFBR2 extracellular domain to stimulatory endodomains like CD28, researchers can shield T cells from inhibition or even repurpose TGF-beta as an activating signal (PubMed: 29305544, PubMed: 32661326). This modification enhances the survival, proliferation, and cytotoxic activity of CAR-T or TCR-T cells against solid tumors. Clinical trials are currently evaluating these engineered complexes in various malignancies, including prostate cancer and glioblastoma, to improve therapeutic outcomes where standard immunotherapies have failed (ClinicalTrials.gov NCT03089229).

Other names

TGF-beta receptor type IITGFBR2Dominant-negative TGF-beta receptor IIdnTGFBRIITGF-beta switch receptorTGFBR2-CD28 chimeric receptor

The signaling complex is modified in engineered T cells to either block inhibitory TGF-beta signaling via dominant-negative receptors (dnTGFBRII) or to convert inhibitory signals into stimulatory ones via chimeric switch receptors (e.g., TGFBR2-CD28), thereby enhancing T cell persistence and anti-tumor activity within the immunosuppressive tumor microenvironment.