Human leukocyte antigen A*02:01-restricted X-box binding protein 1 spliced peptide (367-375) (HLA-A2/XBP-1s(367-375))

The HLA-A2–presented XBP-1SP367-375 epitope is a peptide-major histocompatibility complex (pMHC) consisting of a 9-amino acid sequence (YLFPQLISL) derived from the spliced isoform of X-box binding protein 1 (XBP-1s) presented by the HLA-A*02:01 allele (Bae et al., Blood, 2011). XBP-1s is a potent transcription factor that regulates the unfolded protein response (UPR) and is essential for plasma cell differentiation and survival (UniProt P17861). In malignancies such as multiple myeloma and Waldenström macroglobulinemia, XBP-1s is constitutively overexpressed to manage high levels of protein synthesis and endoplasmic reticulum stress (Bae et al., Leukemia, 2012). Because the spliced region of XBP-1 is unique to the active isoform and highly enriched in tumor cells, this epitope serves as a tumor-associated antigen with high specificity. Therapeutic interventions, including the multi-peptide vaccine PVX-410 and various T-cell receptor (TCR)-based therapies, target this complex to elicit a cytotoxic T-lymphocyte (CTL) response against cancer cells (ClinicalTrials.gov NCT01718899). Clinical studies have shown that targeting this epitope can induce durable immune responses and clinical activity in patients with early-stage or relapsed/refractory plasma cell dyscrasias (Bae et al., OncoImmunology, 2015). The epitope is specifically recognized by the T-cell receptor of CD8+ T cells, leading to the lysis of HLA-A2+ tumor cells expressing XBP-1s. This target is particularly attractive because XBP-1s is a driver of the malignant phenotype, reducing the likelihood of immune escape through antigen loss.

Other names

XBP1s 367-375XBP1 SP 367-375YLFPQLISL peptideHLA-A*02:01/XBP1s(367-375)XBP-1 spliced peptide 367-375

Induction of cytotoxic T-lymphocyte (CTL) response and T-cell activation