Pancreatic and duodenal homeobox 1 (PDX1) (PDX1)

Pancreatic and duodenal homeobox 1 (PDX1) is a homeodomain-containing transcription factor that plays a critical role in the early development of the pancreas and the maintenance of mature beta-cell function. While its expression is restricted to the pancreas and certain areas of the duodenum in adults, it is frequently overexpressed in pancreatic ductal adenocarcinoma (PDAC), where it promotes tumor cell proliferation, survival, and epithelial-mesenchymal transition (EMT). Due to its intracellular localization, PDX1 is not accessible to conventional antibody-based therapies; however, it can be targeted via T-cell receptor (TCR) engineered T cells that recognize PDX1-derived peptides presented on major histocompatibility complex (MHC) molecules. Recent research has identified specific immunogenic PDX1 peptides, such as those restricted to HLA-A*02:01, which can be recognized by high-affinity TCRs to elicit potent anti-tumor responses. Despite its promise as a tumor-associated antigen, targeting PDX1 poses significant safety challenges, most notably the risk of on-target, off-tumor toxicity against normal pancreatic beta cells, which could lead to the development of insulin-dependent diabetes. Current therapeutic strategies are exploring ways to enhance the specificity and safety of PDX1-targeted immunotherapies, including the use of logic-gated circuits or transient TCR expression.

Other names

Insulin promoter factor 1IPF1Somatostatin-transactivating factor 1STF-1Islet-specific transcription factorGlucose-sensitive factorGSFIDX-1IUF1

T-cell receptor (TCR) mediated recognition of PDX1-derived peptide-MHC complexes on the surface of cancer cells, leading to T-cell activation, cytokine release, and tumor cell lysis.