Blood-Based Immunoglobulin-Bound Neoantigen Signatures Associated with MEN Type 1-Related Duodenopancreatic Neuroendocrine Tumor Progression.

Duodenopancreatic neuroendocrine tumors (dpNETs) are a frequent manifestation in patients with MEN type 1 (MEN1), and metastatic dpNETs are the primary cause of mortality. We evaluated a humoral response in the form of immunoglobulin (Ig)-bound antigens that are associated with dpNET development and progression in patients with MEN1. Proteomic analysis of plasma Ig-bound proteins was performed in a cohort of 42 MEN1 patients with dpNET (28 with indolent disease and 14 with liver metastasis) and 14 MEN1 patients without dpNETs. Ingenuity Pathway Analysis and major histocompatibility complex class II binding prediction (NetMHCIIpan) were performed to identify candidate immunogenic antigens and underlying networks. Findings were further compared with proteomics profiles of human pNET tissues. A total of 1,117 Ig-bound proteins were identified. Differential analyses revealed 435 Ig-bound antigens to be enriched (exclusive or fold change 2 or higher) in dpNET patients compared with MEN1 patients without dpNETs, of which 130 were highest in those with a dpNET and liver metastasis. Ingenuity Pathway Analysis of the 435 dpNET-associated Ig-bound antigens revealed cancer, endocrine system disorders, and neurological disease as top predicted disease types, and networks centered on B-cell receptor and T-cell receptor signaling as well as TP53 and transforming growth factor-beta signaling. An intersection of proteomic profiles from human MEN1 pNET tissues revealed 73 overlapping proteins. major histocompatibility complex-II affinity prediction identified SF3B3, ADD2, MDM2, INTS4, and CMTM1 to encompass high-binding immunocore sequences. We have uncovered antigenic protein signatures in the form of a humoral response associated with the development and progression of MEN1-related dpNETs.