Cancer-associated mucins: role in immune modulation and metastasis

Abstract

Mucins (MUC) protect epithelial barriers from environmental insult to maintain homeostasis. However, their aberrant overexpression and glycosylation in various malignancies facilitate oncogenic events from inception to metastasis. Mucin-associated sialyl-Tn (sTn) antigens bind to various receptors present on the dendritic cells (DCs), macrophages, and natural killer (NK) cells, resulting in overall immunosuppression by either receptor masking or inhibition of cytolytic activity. MUC1-mediated interaction of tumor cells with innate immune cells hampers cross-presentation of processed antigens on MHC class I molecules. MUC1 and MUC16 bind siglecs and mask Toll-like receptors (TLRs), respectively, on DCs promoting an immature DC phenotype that in turn reduces T cell effector functions. Mucins, such as MUC1, MUC2, MUC4, and MUC16, interact with or form aggregates with neutrophils, macrophages, and platelets, conferring protection to cancer cells during hematological dissemination and facilitate their spread and colonization to the metastatic sites. On the contrary, poor glycosylation of MUC1 and MUC4 at the tandem repeat region (TR) generates cancer-specific immunodominant epitopes. The presence of MUC16 neo-antigen-specific T cell clones and anti-MUC1 antibodies in cancer patients suggests that mucins can serve as potential targets for developing cancer therapeutics. The present review summarizes the molecular events involved in mucin-mediated immunomodulation, and metastasis, as well as the utility of mucins as targets for cancer immunotherapy and radioimmunotherapy.

Keywords: Cancer; Immunomodulation; Inflammation; Mucins; Vaccine.

Fig. 1

Immunomodulation by tumor-associatedMUC. Tumor-associated mucins (MUC) promote an immunosuppressive microenvironment by either masking Toll-like receptors (TLRs) on antigen-presenting cells (APCs) or inhibiting synapse formation between cytolytic natural killer (NK) cells and cancer cells. Mucins increase immune tolerance by enhancing reprogramming toward a regulatory T cell (T-regs) phenotype and decreasing expression of activation markers on dendritic cells (DCs). Further, mucins activate tumor-specific humoral and cellular immune responses in the presence of adjuvants or TLR agonists. Antibody-dependent cellular cytotoxicity (ADCC), sialyl Tn antigen (sTn), cytotoxic T-lymphocytes (CTLs), interleukin (IL), transforming growth factor beta1 (TGF-β1), and cluster of differentiation (CDs)

Fig. 2

Stages for ADCC, ADC or radiolabeled anti-mucin antibody mediated targeting during cancer progression. Different stages (1–5) during cancer progression and metastasis that are vulnerable to targeting by mucin specific antibody/active fragment(s). ADCC, ADC, and RIT are all dependent on antibody specificity and antigen expression in a particular cancer type. In addition, RIT is shown to be suitable for targeting post resection residual disease (6). Abbreviations: Circulatory tumor cells (CTCs); disseminated tumor cells (DTC); monoclonal antibodies (mAbs). Organ structures are adapted from ChemDraw drawing software