Folate receptor alpha (FRα)-derived peptide presented on HLA-A*02:01 (FRα-HLA-A2)

Folate receptor alpha (FRα), encoded by the FOLR1 gene, is a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein that binds folic acid with high affinity and facilitates its transport into cells via receptor-mediated endocytosis [1]. While its expression in normal tissues is highly restricted to the apical surfaces of certain epithelia (such as the kidney proximal tubules and lung alveoli), it is significantly overexpressed in a variety of solid tumors, including over 80% of ovarian cancers and many non-small cell lung cancers [2]. In the context of TCR-based immunotherapy, intracellular FRα protein is degraded by the proteasome into short peptides, which are then transported to the endoplasmic reticulum and loaded onto Human Leukocyte Antigen (HLA) class I molecules, specifically HLA-A*02:01 [3]. This peptide-MHC complex is subsequently presented on the cell surface, where it can be recognized by engineered T-cell receptors (TCRs) on the surface of therapeutic T-cells [4]. Unlike monoclonal antibodies or antibody-drug conjugates (ADCs) that target the extracellular domain of the intact protein, TCR-based therapies targeting the FRα-HLA-A2 complex allow for the recognition of tumor cells based on internal protein processing, potentially offering higher sensitivity and a different safety profile [5]. Current therapeutic strategies focusing on this target include TCR-engineered T-cells (TCR-T) and TCR-bispecific engagers designed to redirect the immune system to eliminate FRα-positive malignant cells [4, 5]. Sources: [1] UniProt, P15328 (FOLR1_HUMAN), https://www.uniprot.org/uniprotkb/P15328/entry [2] Scaranti, M., et al. (2020). Folate receptor alpha: a medical review. Nature Reviews Clinical Oncology. https://doi.org/10.1038/s41571-020-0339-5 [3] Kim, D. K., et al. (2012). Identification of HLA-A2-restricted folate receptor alpha-derived cytotoxic T-lymphocyte epitopes. International Journal of Oncology. https://doi.org/10.3892/ijo.2012.1363 [4] Schuster, S. J., et al. (2021). T cell receptor-engineered T cells for cancer treatment. Frontiers in Immunology. https://doi.org/10.3389/fimmu.2021.601570 [5] Lu, Y., et al. (2019). Folate receptor-targeted immunotherapy: the next generation of cancer treatment. Trends in Cancer. https://doi.org/10.1016/j.trecan.2019.01.002

Other names

FOLR1Folate receptor 1FR-alphaFolate-binding protein 1FRα peptide-MHC complexKB cells antigen

T-cell receptor (TCR) recognition of the specific FRα-derived peptide (e.g., FRα191) presented on the HLA-A*02:01 molecule, triggering T-cell activation, secretion of cytotoxic granules (perforin/granzyme), and apoptosis of the target cancer cell.