MUCIN-4 (MUC4) is a novel tumor antigen in pancreatic cancer 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.

Keywords: Immunotherapy; MUC4; Neoantigen; Pancreatic cancer; Vaccine.

Figure 1.. Pancreatic tumor microenvironment (TME) and immunosuppression.

Pancreatic tumor microenvironment, in addition to disrupted transport system, is comprised of physical and biochemical barriers including high interstitial fluid pressure (IEF), hypoxia, acidic pH along with cellular infiltrates including fibroblasts, cancer stem cells tumor associated macrophages (TAMs), and other immune cells (A-C). Both cellular and acellular components in pancreatic tumor including regulatory T and B cells, myeloid derived suppressive cells (MDSCs), TAMs, other suppressive immune cells, and their secreted cytokines contribute to the immunosuppression (D). The immunosuppression and high desmoplasia are major challenges to PC immunotherapy.

Figure 2:. Immunological significance of MUC4 in pancreatic cancer.

(A) MUC4 expression is absent in the normal pancreas, whereas the expression begins as early as neoplastic changes (PanINs) occur following oncogenic mutation. MUC4 expression gradually increases from PanINs to PDAC (B) Different studies showing MUC4 specific immune response in PC preclinical settings. The predicted T-cell epitopes as well as recombinant subunit of MUC4 have been evaluated in different settings to test the utility of MUC4 as a vaccine candidate.

Figure 3.. Analysis of MUC4 immunogenicity.

(A) The mutational profile of MUC4 antigen in PDA patients was analyzed in TCGA dataset and observed somatic mutations are highlighted in red. Somatic mutations V868I and G4932R are present in N-terminus (subunit-α) and C-terminus (subunit-β) respectively (B) Multiple putative 9-mer immunogenic peptides on chromosome 3 were predicted by using NetCTL and IEDB prediction methods (binding affinity ≤500nM). The red and blue lines show the exon boundaries and the figure shows both exons and introns that are present in MUC4 sequence.