Transforming growth factor beta receptor type 2 frameshift mutation-derived peptide presented on HLA-A*02:01 (TGFBR2-FS-HLA-A2)

The Transforming growth factor beta receptor type 2 (TGFBR2) frameshift mutation-derived peptide presented on HLA-A*02:01 is a prominent neoantigen target in oncology, particularly for tumors characterized by microsatellite instability (MSI-H) (Markowitz et al., 1995). In these cancers, the loss of DNA mismatch repair leads to a characteristic 1-base pair deletion in the polyadenine (A10) tract of the TGFBR2 gene, resulting in a novel, non-self C-terminal peptide sequence (Saeterdal et al., 2001). This frameshifted peptide, often the 9-mer RLSSCVPVA, is processed and presented by the HLA-A*02:01 molecule, making it a highly specific target for the immune system (Linette et al., 2019). Because this sequence is entirely absent from the normal human proteome, it serves as an ideal target for immunotherapies such as cancer vaccines and T-cell receptor (TCR) engineered T-cell therapies, with a low risk of off-target toxicity. Clinical development is focused on MSI-H colorectal, gastric, and endometrial cancers where these mutations are highly prevalent (Kloor & von Knebel Doeberitz, 2016). Current drugs in development, such as the multi-neoantigen vaccine Nous-209, specifically include this peptide to induce a robust cytotoxic T-lymphocyte response (D'Alise et al., 2022). However, therapeutic challenges include potential immune evasion through the downregulation of the HLA presentation machinery in advanced tumors.

Other names

TGFBR2 frameshift neoantigenTGFBR2-FS peptideHLA-A2/TGFBR2-FS complexRLSSCVPVA-HLA-A*02:01 complex

Induction of a targeted cytotoxic T-lymphocyte response against tumor cells presenting the frameshifted TGFBR2 peptide via vaccine-mediated priming or adoptive T-cell transfer (Linette et al., 2019; D'Alise et al., 2022).