MUCIN-4 (MUC4) is a novel tumor antigen in pancreatic cancer immunotherapy. (February 2020) - Gautam, Shailendra K.
Highlights: Lack of neoantigens, obstructive stroma and immunosuppressive microenvironment are the major challenges for immunotherapy of PC. MUC4, due to its overexpression, aberrant glycosylation, and existence of splice variants, is an attractive target for immunotherapy. Bioinformatic analysis of PC patient datasets reveals presence of somatic mutations in MUC4 antigen. Initial studies evaluating the potential of MUC4 as target for immunotherapy utilized predicted T-cell epitopes, and recombinant fragments. Lack of suitable animal models has hampered the development of MUC4-targeted immunotherapy. Abstract: Pancreatic cancer (PC) is a highly lethal malignancy with a dismal five-year survival rate. This is due to its asymptomatic nature, lack of reliable biomarkers, poor resectability, early metastasis, and high recurrence rate. Limited efficacies of current treatment modalities treatment-associated toxicity underscore the need for the development of immunotherapy-based approaches. For non-resectable, locally advanced metastatic PC, immunotherapy-based approaches including vaccines, antibody-targeted, immune checkpoint inhibition, CAR-T-cells, and adoptive T-cell transfer could be valuable additions to existing treatment modalities. Thus far, the vaccine candidates in PC have demonstrated modest immunological responses in different treatment modalities. The identification of tumor-associated antigens (TAA) and their successful implication in PC treatment is still a challenge. MUC4, a high molecular weight glycoprotein that functionally contributes to PC pathogenesis, is an attractive TAA. It is not detected in the normal pancreas; however, it is overexpressed in mouse and human pancreatic tumors. The recombinant MUC4 domain, as well as predicted immunogenic T-cell epitopes, elicited cellular and humoral anti-MUC4 response, suggesting its ulility as a vaccine candidate for PC therapy. Existence of PC-associated MUC4 splice variants, autoantibodies against overexpressed and aberrantly glycosylated MUC4 and presence of T-cell clones against the mutations present in MUC4 further reinforce its significance as a tumor antigen for vaccine development. Herein, we review the significance of MUC4 as a tumor antigen in PC immunotherapy and discuss both, the development and challenges associated with MUC4 based immunotherapy. Lastly, we will present our perspective on MUC4 antigenicity for the future development of MUC4-based PC immunotherapy.