Transforming growth factor-beta receptor type 2 signaling complex (TGFBR2 signaling complex)

The Transforming growth factor-beta receptor type 2 (TGFBR2) signaling complex is a pivotal regulator of immune responses, particularly within the immunosuppressive landscape of the tumor microenvironment (UniProt P37173). In healthy tissues, TGFBR2 binds TGF-beta ligands to initiate a signaling cascade through TGFBR1 and SMAD proteins, regulating cell growth and differentiation. However, in many solid tumors, high levels of TGF-beta exploit this pathway to inhibit T-cell activation, promote exhaustion, and evade immune surveillance (PubMed: 29311297). To counter this, engineered T-cell therapies, such as CAR-T cells, are designed to modify the TGFBR2 signaling complex, often through the expression of a dominant-negative receptor (dnTGFBRII) or CRISPR-mediated gene knockout (PubMed: 30305464). These modifications prevent the T cells from responding to inhibitory TGF-beta signals, thereby enhancing their potency, survival, and ability to infiltrate and destroy solid tumors. Clinical candidates like P-PSMA-101 utilize these modifications to improve the efficacy of CAR-T cells against prostate cancer (ClinicalTrials.gov: NCT04249947). By disrupting the TGFBR2 signaling axis, researchers aim to enhance T-cell persistence and overcome the biological barriers presented by the tumor microenvironment.

Other names

TGF-beta receptor type IITGFBR2TGFR-2TGF-beta receptor 2Dominant-negative TGF-beta receptor IIdnTGFBRIITGF-beta signaling axis

Competitive inhibition of TGF-beta signaling via dominant-negative receptors or genetic ablation to prevent T-cell suppression.