Mucin Antigen Research Articles

Enhancing T Cell and Antibody Response in Mucin-1 Transgenic Mice through Co-Delivery of Tumor-Associated Mucin-1 Antigen and TLR Agonists in C3-Liposomes.

Mucin-1 (MUC1) is a highly relevant antigen for cancer vaccination due to its overexpression and hypo-glycosylation in a high percentage of carcinomas. To enhance the immune response to MUC1, our group has developed C3-liposomes that encapsulate the MUC1 antigen along with immunostimulatory compounds for direct delivery to antigen-presenting cells (APCs). C3-liposomes bind complement C3, which interacts with C3-receptors on APCs, resulting in liposomal uptake and the delivery of tumor antigens to APCs in a manner that mimics pathogenic uptake. In this study, MUC1 and Toll-like receptor (TLR) agonists were encapsulated in C3-liposomes to provoke an immune response in transgenic mice tolerant to MUC1. The immune response to the C3-bound MUC1 liposomal vaccine was assessed by ELISA, ELISpot, and flow cytometry. Co-administering TLR 7/8 agonists with MUC1 encapsulated in C3-liposomes resulted in a significant antibody response compared to non-encapsulated MUC1. This antibody response was significantly higher in females than in males. The co-encapsulation of three TLR agonists with MUC1 in C3-liposomes significantly increased antibody responses and eliminated sex-based differences. Furthermore, this immunization strategy resulted in a significantly increased T cell-response compared to other treatment groups. In conclusion, the co-delivery of MUC1 and TLR agonists via C3-liposomes greatly enhances the immune response to MUC1, highlighting its potential for antigen-specific cancer immunotherapy.

Tumor Markers and Their Prognostic Value in Sinonasal ITAC/Non-ITAC.

One of the rare tumor entities present in the nose and paranasal sinuses is sinonasal (non-) intestinal-type adenocarcinoma (ITAC/non-ITAC). Currently, surgery with postoperative radiotherapy is the cornerstone of the treatment of these tumors. Systemic treatment is usually applied in a palliative setting. The prognosis of these tumors is very diverse. Biomarkers that may have prognostic value in these rare malignancies could help clinicians in decision-making. A systematic search of the literature was performed using the PubMed database. All studies investigating the prognostic significance of biomarkers in paranasal sinus ITAC/non-ITAC were retrieved. The findings were categorized within the hallmarks of cancer, to gain an understanding of the functions of possible prognostic biomarkers in the development of ITAC/non-ITAC. There were twenty-one studies reporting on twenty-one possible biomarkers included in the review. The expression of Mucin antigen sialosyl-Tn, C-erbB-2 oncoprotein, TIMP3 methylation, TP53, VEGF, ANXA2, MUC1 and the mucinous histological subtype were found to have a significant negative effect on survival. None of the biomarkers were found to have a positive effect on prognosis. The hallmarks 'activating invasion and metastasis' and 'sustaining proliferative signaling' seem to play the largest role in sinonasal (non-)ITAC. It could be concluded that there are multiple biomarkers foreboding a negative prognosis for ITAC/non-ITAC patients.

Niosomes as Biocompatible Scaffolds for the Multivalent Presentation of Tumor-Associated Antigens (TACAs) to the Immune System.

Fully synthetic tumor-associated carbohydrate antigen (TACA)-based vaccines are a promising strategy to treat cancer. To overcome the intrinsic low immunogenicity of TACAs, the choice of the antigens' analogues and multivalent presentation have been proved to be successful. Here, we present the preparation, characterization, and in vitro screening of niosomes displaying multiple copies of the mucin antigen TnThr (niosomes-7) or of TnThr mimetic 1 (niosomes-2). Unprecedentedly, structural differences, likely related to the carbohydrate portions, were observed for the two colloidal systems. Both niosomal systems are stable, nontoxic and endowed with promising immunogenic properties.

Breast Cancer Vaccine Containing a Novel Toll-like Receptor 7 Agonist and an Aluminum Adjuvant Exerts Antitumor Effects

Mucin 1 (MUC1) has received increasing attention due to its high expression in breast cancer, in which MUC1 acts as a cancer antigen. Our group has been committed to the development of small-molecule TLR7 (Toll-like receptor 7) agonists, which have been widely investigated in the field of tumor immunotherapy. In the present study, we constructed a novel tumor vaccine (SZU251 + MUC1 + Al) containing MUC1 and two types of adjuvants: a TLR7 agonist (SZU251) and an aluminum adjuvant (Al). Immunostimulatory responses were first verified in vitro, where the vaccine promoted the release of cytokines and the expression of costimulatory molecules in mouse BMDCs (bone marrow dendritic cells) and spleen lymphocytes. Then, we demonstrated that SZU251 + MUC1 + Al was effective and safe against a tumor expressing the MUC1 antigen in both prophylactic and therapeutic schedules in vivo. The immune responses in vivo were attributed to the increase in specific humoral and cellular immunity, including antibody titers, CD4+, CD8+ and activated CD8+ T cells. Therefore, our vaccine candidate may have beneficial effects in the prevention and treatment of breast cancer patients.

Cover Feature: Structurally Constrained MUC1‐Tn Mimetic Antigen as Template for Molecularly Imprinted Polymers (MIPs): A Promising Tool for Cancer Diagnostics (ChemPlusChem 9/2022)

The cover feature image shows the possibility to replace the use of monoclonal antibodies with an innovative class of catecholamine-based Molecularly Imprinted Polymers (MIPs). MIPs are synthetic receptors characterized by high sensitivity and specificity towards the imprinted target. Here, the imprinted targets are the native TnThr mucin antigen, over-expressed in several adenocarcinomas including the very aggressive Triple Negative Breast Cancer (TNBC), and the structurally locked TnThr mimetic. Cover design by Francesco Papi. More information can be found in the Research Article by C. Nativi, S. Scarano, and co-workers.

PNA-Modified Liposomes Improve the Delivery Efficacy of CAPIRI for the Synergistic Treatment of Colorectal Cancer.

Tumor-associated antigen mucin 1 (MUC1) is highly expressed in colorectal cancer and is positively correlated with advanced stage at diagnosis and poor patient outcomes. The combination of irinotecan and capecitabine is standard chemotherapy for metastatic colorectal cancer and is known as XELIRI or CAPIRI, which significantly prolongs the progression-free survival and overall survival of colorectal cancer patients compared to a single drug alone. We previously reported that peanut agglutinin (PNA)-conjugated liposomes showed enhanced drug delivery efficiency to MUC1-positive liver cancer cells. In this study, we prepared irinotecan hydrochloride (IRI) and capecitabine (CAP)-coloaded liposomes modified by peanut agglutinin (IRI/CAP-PNA-Lips) to target MUC1-positive colorectal cancer. The results showed that IRI/CAP-PNA-Lips showed an enhanced ability to target MUC1-positive colorectal cancer cells compared to unmodified liposomes. Treatment with IRI/CAP-PNA-Lips also increased the proportion of apoptotic cells and inhibited the proliferation of colorectal cancer cells. The targeting specificity for tumor cells and the antitumor effects of PNA-modified liposomes were significantly increased in tumor-bearing mice with no severe cytotoxicity to normal tissues. These results suggest that PNA-modified liposomes could provide a new delivery strategy for the synergistic treatment of colorectal cancer with clinical chemotherapeutic agents.

A CURE for Cloning: Implementing a Modular Approach to Cloning Recombinant Antibodies in an Undergraduate Teaching Lab

An undergraduate course‐based research experience (CURE) is a high impact practice which provides genuine research experiences to a large and diverse student population. We have implemented a six‐week research module involving the cloning and expression of therapeutic antibodies as the culmination of a senior level Biochemistry lab course. We have designed a cloning system that takes advantage of the modular domain structure of antibodies to facilitate changes to an antibody’s affinity, isotype, or allotype. Specifically, our system was developed for readily swapping the antigen‐binding N‐terminal sequences of different antibodies into a set of vectors encoding the conserved regions of the heavy and light chains, all in the background of a strong mammalian expression vector. Gene fragments corresponding to the constant regions of each immunoglobulin chain, as well as the antigen‐binding regions of unique antibodies were designed, and produced by gene synthesis. Various iterations of the module were tested over four different semesters with high levels of success in terms of student engagement and research goals. The resulting plasmid constructs are now being used by our research lab as part of the investigation of the nature of antibody recognition of cancer‐specific Mucin antigens. This project allowed our senior undergraduates to contribute to an active research program, while earning credit toward a required course. It exposed them to modern cloning methodologies, bioinformatics tools, cell culture techniques and participation in a local research conference. It is also a readily scalable project as only the variable regions of new antibodies of interest need be synthesized.

Alum Adjuvant and Built-in TLR7 Agonist Synergistically Enhance Anti-MUC1 Immune Responses for Cancer Vaccine.

The tumor-associated antigen mucin 1 (MUC1) is an attractive target of antitumor vaccine, but its weak immunogenicity is a big challenge for the development of vaccine. In order to enhance immune responses against MUC1, herein, we conjugated small molecular toll-like receptor 7 agonist (TLR7a) to carrier protein BSA via MUC1 glycopeptide to form a three-component conjugate (BSA-MUC1-TLR7a). Furthermore, we combined the three-component conjugate with Alum adjuvant to explore their synergistic effects. The immunological studies indicated that Alum adjuvant and built-in TLR7a synergistically enhanced anti-MUC1 antibody responses and showed Th1-biased immune responses. Meanwhile, antibodies elicited by the vaccine candidate effectively recognized tumor cells and induced complement-dependent cytotoxicity. In addition, Alum adjuvant and built-in TLR7a synergistically enhanced MUC1 glycopeptide-specific memory CD8+ T-cell immune responses. More importantly, the vaccine with the binary adjuvant can significantly inhibit tumor growth and prolong the survival time of mice in the tumor challenge experiment. This novel vaccine construct provides an effective strategy to develop antitumor vaccines.

MUC1 Specific Immune Responses Enhanced by Coadministration of Liposomal DDA/MPLA and Lipoglycopeptide.

Mucin 1 (MUC1), a well-known tumor-associated antigen and attractive target for tumor immunotherapy, is overexpressed in most human epithelial adenomas with aberrant glycosylation. However, its low immunogenicity impedes the development of MUC1-targeted antitumor vaccines. In this study, we investigated three liposomal adjuvant systems containing toll-like receptor 4 (TLR4) agonist monophosphoryl lipid A (MPLA) and auxiliary lipids of different charges: cationic lipid dimethyldioctadecylammonium (DDA), neutral lipid distearoylglycerophosphocholine (DSPC) or anionic lipid dioleoylphosphatidylglycerol (DOPG), respectively. ELISA assay evidenced that the positively charged DDA/MPLA liposomes are potent immune activators, which induced remarkable levels of anti-MUC1 antibodies and exhibited robust Th1-biased immune responses. Importantly, the antibodies induced by DDA/MPLA liposomes efficiently recognized and killed MUC1-positive tumor cells through complement-mediated cytotoxicity. In addition, antibody titers in mice immunized with P2-MUC1 vaccine were significantly higher than those from mice immunized with P1-MUC1 or MUC1 vaccine, which indicated that the lipid conjugated on MUC1 antigen also played important role for immunomodulation. This study suggested that the liposomal DDA/MPLA with lipid-MUC1 is a promising antitumor vaccine, which can be used for the immunotherapy of various epithelial carcinomas represented by breast cancer.

Comparative ligand structural analytics illustrated on variably glycosylated MUC1 antigen-antibody binding.

When faced with the investigation of the preferential binding of a series of ligands against a known target, the solution is not always evident from single structure analysis. An ensemble of structures generated from computer simulations is valuable; however, visual analysis of the extensive structural data can be overwhelming. Rapid analysis of trajectory data, with tools available in the Galaxy platform, can be used to understand key features and compare differences that inform the preferential ligand structure that favors binding. We illustrate this informatics approach by investigating the in-silico binding of a peptide and glycopeptide epitope of the glycoprotein Mucin 1 (MUC1) binding with the antibody AR20.5. To study the binding, we performed molecular dynamics simulations using OpenMM and then used the Galaxy platform for data analysis. The same analysis tools are applied to each of the simulation trajectories and this process was streamlined by using Galaxy workflows. The conformations of the antigens were analyzed using root-mean-square deviation, end-to-end distance, Ramachandran plots, and hydrogen bonding analysis. Additionally, RMSF and clustering analysis were carried out. These analyses were used to rapidly assess key features of the system, interrogate the dynamic structure of the ligand, and determine the role of glycosylation on the conformational equilibrium. The glycopeptide conformations in solution change relative to the peptide; thus a partially pre-structuring is seen prior to binding. Although the bound conformation of peptide and glycopeptide is similar, the glycopeptide fluctuates less and resides in specific conformers for more extended periods. This structural analysis which gives a high-level view of the features in the system under observation, could be readily applied to other binding problems as part of a general strategy in drug design or mechanistic analysis.

Immunohistochemical and genetic analysis of respiratory epithelial adenomatoid hamartomas and seromucinous hamartomas: are they precursor lesions to sinonasal low-grade tubulopapillary adenocarcinomas?

Respiratory epithelial adenomatoid hamartoma (REAH) and seromucinous hamartoma (SH) are rare tumor-like lesions of the nasal cavity, paranasal sinuses, and nasopharynx. The pathogenesis of REAH/SH is still unclear. Neoplastic proliferation, chronic mechanical irritation, inflammation, or possible embryological tissue misplacement are speculated as possible mechanisms of their development. Low-grade tubulopapillary adenocarcinoma (LGTA) is a rare variant of nonsalivary, nonintestinal type sinonasal adenocarcinoma. The aim of this study was to evaluate the immunohistochemical and genetic profiles of 10 cases of REAH/SH, with serous, mucinous, and respiratory components evaluated separately and to compare these findings with the features of 9 cases of LGTA. All cases of REAH/SH and LGTA were analyzed immunohistochemically with a cocktail of mucin antigens (MUC1, MUC2, MUC4, MUC5AC, MUC6) and with epithelial (CK7, CK20, CDX2, SATB2) and myoepithelial markers (S100 protein, p63, SOX10). The next-generation sequencing assay was performed using FusionPlex Solid Tumor Kit (ArcherDx) in 10 cases of REAH/SH, and the EGFR-ZNF267 gene fusion was detected in 1 of them. Two female REAH/SH cases were assessed for the presence of clonality. Using the human androgen receptor assay, 1 case was proved to be clonal. The serous component of REAH/SH was positive for CK7/MUC1 and SOX10 similarly to LGTA. Although REAH/SH and LGTA are histopathologically and clinically separate entities, the overlap in their morphological and immunohistochemical profiles suggests that REAH/SH might be a precursor lesion of LGTA.

Liposomal Antitumor Vaccines Targeting Mucin 1 Elicit a Lipid-Dependent Immunodominant Response.

The tumor-associated antigen mucin 1 (MUC1) has been pursued as an attractive target for cancer immunotherapy, but the poor immunogenicity of the endogenous antigen hinders the development of vaccines capable of inducing effective anti-MUC1 immunodominant responses. Herein, we prepared synthetic anti-MUC1 vaccines in which the hydrophilic MUC1 antigen was N-terminally conjugated to one or two palmitoyl lipid chains (to form amphiphilic Pam-MUC1 or Pam2 -MUC1). These amphiphilic lipid-tailed MUC1 antigens were self-assembled into liposomes containing the NKT cell agonist αGalCer as an adjuvant. The lipid-conjugated antigens reshaped the physical and morphological properties of liposomal vaccines. Promising results showed that the anti-MUC1 IgG antibody titers induced by the Pam2 -MUC1 vaccine were more than 30- and 190-fold higher than those induced by the Pam-MUC1 vaccine and the MUC1 vaccine without lipid tails, respectively. Similarly, vaccines with the TLR1/2 agonist Pam3 CSK4 as an adjuvant also induced conjugated lipid-dependent immunological responses. Moreover, vaccines with the αGalCer adjuvant induced significantly higher titers of IgG antibodies than vaccines with the Pam3 CSK4 adjuvant. Therefore, the non-covalent assembly of the amphiphilic lipo-MUC1 antigen and the NKT cell agonist αGalCer as a glycolipid adjuvant represent a synthetically simple but immunologically effective approach for the development of anti-MUC1 cancer vaccines.

Abstract P4-06-20: Delivering tumour antigens survivin and mucin-1 on virus-like particles for breast cancer immunotherapy

Abstract Breast cancer is the most frequently diagnosed cancer in women worldwide. Although there are a variety of treatment options available, breast cancer is a difficult disease to treat and many patients experience recurrence following treatment. We have previously shown that tumour antigens delivered on virus-like particles (VLP) induce a targeted anti-cancer immune response. In this study we investigated whether combining the two tumour antigens survivin and mucin 1 as vaccine targets can induce a superior anti-cancer immune response for breast cancer immunotherapy. VLP were designed to recombinantly express the murine survivin epitope. Following expression of Survivin-VLP, aberrantly glycosylated mucin 1 (MUC1) peptide was conjugated onto the Survivin-VLP using intracellular cleavable bis-arylhydrazone linking strategy. Western Blot analysis and electron microscopy confirmed Survivin-VLP expression and UV absorption confirmed conjugation of the MUC1 peptide to the Survivin-VLP. C57mg.MUC1 breast cancer cells were injected into the mammary fat pad of C57Bl/6 and MUC1 transgenic mice. Once tumours were palpable, mice were vaccinated with the Survivin-MUC1-VLP and controls of DPBS, VLP without antigen or VLP delivering either survivin or MUC1 antigen. Tumour growth and mouse survival were monitored for 80 days. Mice vaccinated with Survivin-MU1-VLP delivering both antigens showed enhanced survival (D78) compared to mice vaccinated with VLP delivering only one of the antigens (D66) and controls (D53). Delivery of two tumour antigens induced an enhanced anti-tumour immune response compared to delivery of single tumour antigens. The induction of multiple immune responses against different tumour antigens may apply additional evolutionary pressure upon tumours, prolonging the ability for tumours to develop resistance, or escape through the proliferation of a resistant subpopulation. The use of VLP for the delivery of multiple antigens and adjuvants represents a promising approach to improve cancer immunotherapy for breast cancer. Citation Format: Kramer K, Braeden D, Young VL, Walker GF, Ward VK, Young SL. Delivering tumour antigens survivin and mucin-1 on virus-like particles for breast cancer immunotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-06-20.

Novel roles for mucin 1 in the kidney.

Recent studies in the kidney have revealed that the well characterized tumor antigen mucin 1 (MUC1/Muc1) also has numerous functions in the normal and injured kidney. Mucin 1 is a transmembrane mucin with a robust glycan-dependent apical targeting signal and efficient recycling from endosomes. It was recently reported that the TRPV5 calcium channel is stabilized on the cell surface by galectin-dependent cross-linking to mucin 1, providing a novel mechanism for regulation of ion channels and normal electrolyte balance.Our recent studies in mice show that Muc 1 is induced after ischemia, stabilizing hypoxia-inducible factor 1 (HIF-1)α and β-catenin levels, and transactivating the HIF-1 and β-catenin protective pathways. However, prolonged induction of either pathway in the injured kidney can proceed from apparent full recovery to chronic kidney disease. A very recent report indicates that aberrant activation of mucin 1 signaling after ischemic injury in mice and humans is associated with development of chronic kidney disease and fibrosis. A frameshift mutation in MUC1 was recently identified as the genetic lesion causing medullary cystic kidney disease type 1, now appropriately renamed MUC1 Kidney Disease. Studies of mucin 1 in the kidney now reveal significant functions for the extracellular mucin-like domain and signaling through the cytoplasmic tail.

Immunohistochemical expression profiles of mucin antigens in salivary gland mucoepidermoid carcinoma: MUC4- and MUC6-negative expression predicts a shortened survival in the early postoperative phase.

In mucoepidermoid carcinoma (MEC), the most common salivary gland carcinoma, there is a lack of novel prognostic markers, but post-operative early recurrence strongly affects the clinical course and a poor outcome. It is critical to predict which MEC patients are prone to develop recurrence/metastases. Mucins play pivotal roles in influencing cancer biology, thus affecting cell differentiation, adhesion, carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to elucidate the significance of expression profiles for mucins, particularly MUC4 and MUC6, and their correlations with various clinicopathological features and recurrence in salivary gland MECs. We performed immunohistochemical analyses on patients with surgically resected primary MEC using antibodies against mucin core proteins MUC4/8G7 and MUC6/CLH5 in 73 paraffin-embedded samples. Recurrence was noted in 15 of 73 (20.5%) patients. MUC4 or MUC6 expression was considered to be negative when <30% or 0% of the MEC cells showed positive staining, respectively. MUC4- and/or MUC6-negative expression respectively and variably showed a significant relationship to pathological tumor high-grade, the presence of lymphovascular invasion, lymph node metastasis and/or tumor-related death. In addition, MUC4 showed significantly negative co-expression with MUC6. Kaplan-Meier analyses revealed that not only single MUC4/6-negative expression but also the combination of both predicted significantly shorter disease-free and disease-specific survivals in MECs, especially within the first two years postoperatively. Therefore, each mucin plays a pivotal role in the pathogenesis of MEC progression. The detection of MUC4 and/or MUC6 might be a powerful parameter in the clinical management of MECs in the early postsurgical phase.

Immunohistochemical expression of mucin antigens in gallbladder adenocarcinoma: MUC1-positive and MUC2-negative expression Is associated with vessel invasion and shortened survival.

Mucins play pivotal roles in influencing cancer biology, for example affecting carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to investigate the significance of expression profiles of two mucins in particular, MUC1 and MUC2, their correlations with various clinicopathological features, and prognosis in gallbladder adenocarcinoma (GBAC). We performed immunohistochemistry from patients with surgically resected GBAC, using antibodies against mucin core proteins MUC1/DF3 and MUC2/Ccp58 in 81 paraffin-embedded tumor samples. MUC1 or MUC2 expression was considered to be high when ≥ 20% or 10% of the GBAC cells showed positive staining, respectively. High MUC1 expression was revealed to have a significant relationship to the presence of pathologically lymphatic and vascular invasion, and regional lymph node metastasis. By contrast, high MUC2 expression showed a significant correlation with pathologically perineural invasion, T stage ≥ 3, and post-operative recurrence. Moreover, MUC1 showed significantly positive co-expression and potentially complementary correlations with MUC2. Multivariate analyses demonstrated that the high MUC1 expression group had significantly shorter disease-specific survival times. However, the combination of both high MUC1 and MUC2 expression did not predict worse outcome in GBACs. Therefore, although each mucin has a somewhat important role in the pathogenesis of GBAC progression, MUC1 can independently predict vessel invasion and poor prognosis in patients with GBAC. The detection of MUC1 might well offer a useful parameter for providing clinical management and treatment against postsurgical GBACs.

Prognostic Role of Mucin Antigen MUC4 for Cholangiocarcinoma: A Meta-Analysis.

Background and ObjectiveSurgery carries the best hope for cure in the treatment of cholangiocarcinoma (CC), whereas surgical outcome is not fully satisfactory. Bio-molecular markers have been used to improve tumor staging and prognosis prediction. Mucin antigen MUC4 (MUC4) has been implicated as a marker for poor survival in various tumors. However, prognostic significance of MUC4 for patients with CC remains undefined. The aim of the present meta-analysis was to investigate the association between MUC4 expression and overall survival (OS) of patients with resected CC.MethodsThe meta-analysis was conducted in adherence to the MOOSE guidelines. PubMed, Embase databases, Cochrane Library and the Chinese SinoMed were systematically searched to identify eligible studies from the initiation of the databases to April, 2016. OSs were pooled by using hazard ratio (HR) with corresponding 95% confidence interval (CI). Random effect models were utilized because of the between-study heterogeneities.ResultsFive studies reporting on 249 patients were analyzed: 94 (37.75%) were in positive or high expression group and 155 (62.25%) in negative or low expression group. The pooled HR for positive or high expression group was found to be 3.04 (95% CI 2.25–4.12) when compared with negative or low expression group with slight between-study heterogeneities (I2 3.10%, P = 0.39). The result indicated that a positive or high expression level of MUC4 was significantly related to poor survival in patients with resected CC. A commensurate result was identified by sensitivity analysis. The main limitations of the present meta-analysis were the rather small size of the studies included and relatively narrow geographical distribution of population.ConclusionThe result of this meta-analysis indicated that a positive or high expression level of MUC4 was significantly related to poor survival in patients with resected CC.

MUC1 immunotherapy against a metastatic mammary adenocarcinoma model: Importance of IFN-gamma.

Immunotherapy using mucin 1 (MUC1) linked to oxidised mannan (MFP) was investigated in an aggressive MUC1+ metastatic tumour, DA3-MUC1 because, unlike many MUC1+ tumour models, DA3-MUC1 is not spontaneously rejected in mice making it an alternative model for immunotherapy studies. Further, DA3-MUC1 cells are resistant to lysis by anti-MUC1 cytotoxic T cells (CTLs). The inability of DA3-MUC1 tumours to be rejected in naïve mice as well as vaccination to MUC1 was attributed to a deficiency of expression of MHC class I molecules on the tumour cell surface. In vitro and in vivo analysis of subcutaneous tumours and lung metastases demonstrated that DA3-MUC1 tumour cells have a low expression (< 6%) of MHC class I which can be upregulated (> 90%) following culturing with IFN-γ. Results from flow cytometry analysis and immunoperoxidase staining indicated that the in vitro up-regulation of MHC class I could be maintained for up to seven days in vivo, without affecting the expression levels of MUC1 antigen. Interestingly, MUC1-specific CTL that lyse DA3-MUC1 targets in vitro were induced in MFP immunised mice but failed to protect mice from a DA3-MUC1 tumour challenge. These results highlight the importance of MHC class I molecules in the induction of anti-tumour immunity and the MFP immune response.

Prognostic Significance of Mucin Antigen MUC1 in Various Human Epithelial Cancers: A Meta-Analysis.

Accumulating evidence indicates that mucin antigen MUC1 plays a fundamental role in the initiation and progression of several types of epithelial carcinomas. However, whether the expression of MUC1 on tumor cells is associated with patients’ survival remains controversial.Medline/PubMed, EMBASE, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) databases, and Grey literature were searched up to 15 August 2015 for eligible studies of the association between the MUC1 expression and overall survival (OS) in various epithelial cancers. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated from the included studies. Moreover, the odds ratio (OR) was also extracted to evaluate the association between the clinicopathological parameters of participants and MUC1 expression.A total of 3425 patients covering 23 studies were included in the analysis. The pooled results showed that positive MUC1 staining was a negative predictor of OS (HRFEM = 1.98,95% CIFEM: 1.76–2.22, PFEM = 0.479; HRREM = 2.16,95% CIREM: 1.58–2.94, PREM = 0.355) in various epithelial carcinomas. Subgroup analysis revealed that the increased MUC1 expression was significantly associated with poor OS in patients with gastric cancer (HRFEM = 2.12, 95%CIFEM: 1.75–2.57, PFEM = 0.359; HRREM = 1.89, 95% CIREM: 1.05–3.41, PREM = 0.238), colorectal cancer (HRFEM = 1.73, 95%CIFEM: 1.41–2.13, PFEM = 0.048; HRREM = 2.00,95% CIREM: 1.46–2.73, PREM = 0.019), cholangiocarcinoma (HRFEM = 2.52, 95% CIFEM: 1.42–4.49, PFEM = 0.252; HRREM = 2.34, 95% CIREM: 1.30–4.22, PREM = 0.244), and nonsmall cell lung cancer (NSCLC) (HRFEM = 2.14, 95% CIFEM: 1.46–3.14, PFEM = 0.591; HRREM = 2.81, 95% CIREM: 1.40–5.64, PREM = 0.280). In addition, MUC1 overexpression was more likely to be found in colorectal cancer patients with an advanced tumor node metastasis stage (ORREM = 1.55, 95% CIREM: 1.06–2.27; PREM = 0.187) and in gastric cancer patients with positive lymph node metastasis (ORREM = 2.37, 95% CIREM: 1.19–4.73; PREM = 0.004) and intestinal-type classification (ORREM = 2.34, 95% CIREM: 1.59–3.45; PREM = 0.767).Our findings provide evidence that MUC1 detection has a prognostic value in patients with epithelial-originated cancers, especially in NSCLC and gastrointestinal cancers.

Glycopeptide Nanoconjugates Based on Multilayer Self-Assembly as an Antitumor Vaccine.

Antitumor vaccine, which is promising for tumor therapy, has been extensively studied. Some encouraging results of chemically synthetic vaccine designs based on the tumor-associated antigen mucin 1 have been achieved. However, some shortcomings such as low efficiency and difficult purification restrict their clinical application. To overcome these difficulties, we designed a novel antitumor vaccine of glycopeptide nanoconjugates based on the multilayer self-assembly through the interaction of positive and negative charges. This vaccine formed the spherical structure and effectively activated the macrophage in vitro. Besides, it also induced high titer of antibodies against mucin 1 glycopeptide. The induced antibodies could highly bind to the tumor cells and effectively kill them by activation of the complement dependent cytotoxicity complex. This novel strategy provides a new way for the development of simple and effective antitumor vaccine.