针对MUC1黏蛋白DC疫苗的研究进展

树突状细胞(DC)作为抗原递呈细胞在激活肿瘤特异性免疫中发挥重要作用,DC疫苗为肿瘤免疫治疗提供了一种有效手段.MUC1是一种高分子量糖蛋白,属于粘蛋白家族成员,在多种上皮性肿瘤中异常表达,是肿瘤免疫治疗的理想靶抗原.本文综述了MUC1的生物学特征、DC对MUC1的递呈和以MUC1为靶点DC疫苗的抗肿瘤效果.     

Significance of MUC1 and MUC2 mucin expression in colorectal cancer.

AIMS: To compare the lineage specific distribution of MUC1 and MUC2 mucins in normal colorectal mucosa and adenocarcinoma and to identify pathological correlations. METHODS: Paraffin wax sections from 51 colorectal cancers were examined for the expression of MUC1 and MUC2, non-O-acetyl sialic acid and the carbohydrate epitopes Lex, Ley, sialosyl-Lex, sialosyl-Tn, and Tn using standard histochemical methods. RESULTS: MUC1, Lex and Ley co-localised with columnar cell secretions, whereas MUC2, mild periodic acid Schiff and sialosyl-Tn co-localised with goblet cell mucin in both normal and malignant tissues. Sialosyl-Lex and Tn were associated with both lineages. In normal tissues MUC1, Lex and Ley showed only trace expression by crypt base columnar cells. Cancers could be classified into four phenotypes (MUC2+/MUC1-, MUC2+/MUC1+, MUC2-/MUC1+, MUC2-/MUC1-). Particular phenotypes showed significant correlations with cancer type, lymph node spread and peritumoral lymphocytic infiltration and trends falling short of significance in relation to grade of differentiation and contiguous adenoma. CONCLUSIONS: Classification of colorectal cancer by means of lineage specific function may be relevant to both pathogenesis and prognosis.     

MUC1 as a target antigen for cancer immunotherapy

The cancer-associated antigen MUC1 is overexpressed and modified by tumor cells in over half of all cancer cases. Despite various complexities associated with this antigen, it is well worth pursuing as a vaccine for the immunotherapy of cancer. In this review, the authors describe the discovery of MUC1 and its association with cancer, recent observations showing that the immunology of MUC1 is complicated, animal data showing that it can be a target for immune-mediated tumor rejection, and finally, preliminary clinical results to show that vaccine-based immunotherapy with MUC1 does have an impact on the therapy of cancer.     

Dendritic cells in cancer immunotherapy

Antigen presentation is a critical regulatory element for the induction of cellular immune responses. Thus, one of the principal current goals of tumor immunotherapy is to control and enhance tumor antigen presentation. In this respect, dendritic cells (DC) are now being widely investigated as immunotherapeutic agents for the treatment of disseminated malignancies. At present, numerous ways to employ DCs for tumor immunotherapy are being tested, ranging from direct in situ expansion and activation of DCs to adoptive transfer of ex vivo generated DCs, and numerous techniques have been designed to optimize DC activation, tumor antigen delivery to DCs, and induction of tumor-specific, as well as helper immune responses, in vivo. However, the results of recent preclinical studies and the diversity of the clinical phase I trials that are currently underway indicate that little is still known about the exact mechanisms by which DCs modulate tumor immunity and pose the concern that premature clinical trials might not yield the desired results and might be harmful to, rather than promote, the concept of DC-based tumor immunotherapy. This review summarizes some of the current approaches to induce tumor immunity by DC-based vaccination and discusses their advantages and concerns.     

Dendritic cells in cancer immunotherapy

DC initiate and regulate T‐cell immunity and are thus the key to optimization of all types of vaccines. Insights into DC biology offer many opportunities to enhance immunogenicity. In this Viewpoint, I discuss some recent developments and findings that are of immediate relevance for the clinical development of cancer vaccines. In addition, I emphasize my personal view that we should explore the potential of adoptively transferred DC (i.e. DC vaccination) as cancer vaccines by performing two‐armed trials that address critical variables and by delivering antigens via mRNA‐transfected DC.     

Potential for novel MUC1 glycopeptide-specific antibody in passive cancer immunotherapy

Abstract

MUC1 is an important target for antibodies in passive cancer immunotherapy. Antibodies against mucin glycans or mucin peptide backbone alone may give rise to cross reactivity with normal tissues. Therefore, attempts to identify antibodies against cancer-specific MUC1 glycopeptide epitopes havebeen made. We recently demonstrated that a monoclonal antibody against the immunodominant Tn-MUC1 (GalNAc-α-MUC1) antigen induced ADCC in breast cancer cell lines, suggesting the feasibility of targeting combined glycopeptide epitopes in future passive cancer immunotherapy.     

Carbohydrate/peptide mimics: effect on MUC1 cancer immunotherapy

 Recent clinical studies with mannan mucin immunotherapeutic agents indicate that patients produce predominantly antibody responses while mice produce a high cytotoxic T lymphocyte response. In studying the reason for the ’immune deviation’ occurring in mice to humans from cellular to antibody responses, it has been found that natural anti-Galα(1,3)Gal antibodies, present in all humans, react with the mucin component of the agent, providing an example of a carbohydrate-peptide mimic. The immune deviation can be overcome by in vitro sensitization of antigen-presenting cells in the absence of anti-Gal antibodies – at least in mice. The review examines the background of these observations and discusses other peptide carbohydrate mimics and immune deviation Received: 11 January 1999 / Accepted: 22 March 1999     

Dendritic cell immunotherapy for autoimmune diabetes

Dendritic cells (DC) play important roles in the initiation of immune responses and maintenance of self-tolerance. We have been studying the role of DC in the pathogenesis of type 1 diabetes and exploring the ability of specific DC subsets to prevent diabetes in non-obse diabetic (NOD) mice. DC subeets that prevent diabetes in this model have a mature phenotype and induce the production of regulatory Th2 cells. We review here recent advances in this area and highlight the importance of optimizing culture conditions and purification methods in the isolation of therapeutic DC.     

Dendritic cell-based nanovaccines for cancer immunotherapy

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The cell surface mucin MUC1 limits the severity of influenza A virus infection

Cell surface mucin (cs-mucin) glycoproteins are constitutively expressed at the surface of respiratory epithelia where pathogens such as influenza A virus (IAV) gain entry into cells. Different members of the cs-mucin family each express a large and heavily glycosylated extracellular domain that towers above other receptors on the epithelial cell surface, a transmembrane domain that enables shedding of the extracellular domain, and a cytoplasmic tail capable of triggering signaling cascades. We hypothesized that IAV can interact with the terminal sialic acids presented on the extracellular domain of cs-mucins, resulting in modulation of infection efficiency. Utilizing human lung epithelial cells, we found that IAV associates with the cs-mucin MUC1 but not MUC13 or MUC16. Overexpression of MUC1 by epithelial cells or the addition of sialylated synthetic MUC1 constructs, reduced IAV infection in vitro. In addition, Muc1^−/− mice infected with IAV exhibited enhanced morbidity and mortality, as well as greater inflammatory mediator responses compared to wild type mice. This study implicates the cs-mucin MUC1 as a critical and dynamic component of the innate host response that limits the severity of influenza and provides the foundation for exploration of MUC1 in resolving inflammatory disease.     

树突状细胞与肿瘤疫苗

细胞生物学、分子生物学和免疫学等学科的飞速发展,以及新的实验体系和新的技术方法的不断涌现,促进了肿瘤递呈性免疫治疗的日新月异,树突状细胞作为体内功能最强的抗原递呈细胞在以T细胞识别肿瘤抗原为核心的肿瘤生物治疗研究中展现了良好的应用前景。本文通过对树突状细胞在肿瘤疫苗中设计策略的综述,有助于更加准确地看待当今的肿瘤生物治疗。     

Dendritic cells: immunobiology and cancer immunotherapy

A recent workshop on "Dendritic Cells: Biology and Therapeutic Applications," sponsored by the Juan March Foundation, brought together basic and clinical research scientists to discuss the mechanisms underlying the control of immune responses and tolerance by dendritic cells (DCs), as well as recent research in cancer immunotherapy based on DC vaccination. Particular emphasis was placed on antigen processing and presentation by DCs, C-type lectin antigen receptors, DC maturation and polarization of T cell responses, the control of immunity versus tolerance by DCs, the developmental origin of DCs, and the use of DCs in cancer immunotherapy.     

MUC1 mucin: a peacemaker in the lung

MUC1 is a membrane-tethered mucin expressed on the surface of epithelial cells lining mucosal surfaces. Recent studies have begun to elucidate the physiologic function of MUC1 in the airways, pointing to an antiinflammatory role that is initiated late in the course of bacterial infection and is mediated through inhibition of TLR signaling. These new findings have great potential for clinical applications in controlling excessive and prolonged lung inflammation. This review briefly summarizes the protein structural features of MUC1 relevant to its function, the discovery of its antiinflammatory properties, and potential directions for future avenues of study.     

Nanoparticles-based multi-adjuvant whole cell tumor vaccine for cancer immunotherapy

Whole cell tumor vaccine (WCTV), as a potential treatment modality, elicits limited immune responses because of the poor immunogenicity. To address this issue, researchers have attempted to transduce a cytokine adjuvant into tumor cells, but these single-adjuvant WCTVs curtail the high expectations. In present study, we constructed a multi-adjuvant WCTV based on the nanoparticles modified with cell penetrating peptide, which could facilitate the transportation of granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin 2 (IL-2) into tumor cells. After inactivation, as-designed multi-adjuvant WCTV exhibited programmed promotions on DC recruitment, antigen presentation, and T-cell activation. In vivo evaluations demonstrated the satisfactory effects on tumor growth suppression, metastasis inhibition, and recurrence prevention. Therefore, the nanoparticles-based multi-adjuvant WCTV may serve as a high-performance treatment for anti-tumor immunotherapy.     

MHC-restricted presentation of a single repeat of MUC1 mucin

Major histocompatibility complex (MHC) restriction of antigen presentation of a single mucin1 (MUC1) variable number of tandem repeats peptide (VNTR1) was examined by generating cytotoxic T lymphocytes (CTL) derived from peripheral blood mononuclear cells (PBMC) stimulated with a single repeat MUC1 peptide presented by allogeneic (MHC-independent) or autologous (MHC-dependent) Epstein-Barr Virus (EBV) immortalized B lymphocytes. The ability to generate greater CTL activity against MUC1-expressing tumor cells by stimulation with autologous versus allogeneic EBV-B supports the hypothesis that presentation of a single repeat of MUC1 peptide is MHC-restricted (MHC-dependent).     

MUC1 mucin and trefoil factor 1 protein expression in renal cell carcinoma: correlation with prognosis

This study examines the coexpression of MUC1 mucin and trefoil factor 1 (TFF1) and their relationship to progression of renal cell carcinoma (RCC). Immunohistochemistry was performed on tumor and adjacent normal tissue from clear-cell RCC (n = 60) and tissues from normal controls (n = 5) using a set of well-characterized monoclonal antibodies recognizing different epitopes of MUC1 and TFF1. Results of immunohistochemistry were compared with clinical parameters, including tumor grade, tumor size, presence of metastasis, and progression-free survival of patients after surgery. In normal tissue, MUC1 and TFF1 were absent from the normal proximal tubular epithelium but were identified in distal and collecting tubular epithelium. In RCC, increased MUC1 expression positively correlated to tumor progression. MUC1 recognized by HMFG1 was associated with large tumor size (P < .05), distant metastasis (P < .05), and invasion of large veins (P < .05). Expression of the under-glycosylated form of MUC1 recognized by SM3 was found to correlate to time to progression (recurrence, metastasis, or death of patient; P < .001). Expression of TFF1 did not significantly correlate with any prognostic parameters. However, there was a significant correlation (P < .01) between TFF1 and MUC1 expression (HMFG2 epitope) in RCCs. These results are consistent with the following conclusions: (1) MUC1 may be an independent prognostic marker in RCC; (2) TFF1 is frequently coexpressed with MUC1 and may act synergistically; and (3) RCC may originate from distal tubular epithelium.     

双抗体间接夹心ELISA法检测乳腺癌患者外周血MUC1蛋白水平的评价

目的优化双抗体间接夹心ELISA试剂盒,并探讨其在乳腺癌患者中检测MUC1黏蛋白水平的应用价值。方法用基因重组MUC1-GST和MUC1-MBP融和蛋白免疫家兔和大鼠,获得抗MUC1血清,并对其纯化,获得纯化的家兔抗人及大鼠抗人MUC1多克隆抗体;经不同的筛选确立了以家兔抗人MUC1抗体作为包被抗体、大鼠抗人MUC1抗体作为检测抗体的双抗体间接夹心试剂盒,敏感度可达到0.2 ng/ml。结果应用建立的试剂盒对40例乳腺癌,18例乳腺良性疾病和120健康对照者血清中MUC1蛋白水平的进行检测,检测结果绘制ROC曲线,分析得出以2.75 ng/ml为乳腺癌患者与乳腺良性疾病患者的临界值,以1.86 ng/ml为乳腺疾病与正常人为临界值,检测结果表明本研究对乳腺癌诊断的阳性率高达97.5%,乳腺良性疾病的阳性率为66.7%,正常人特异性为96.7%。对于乳腺癌同一病例样本用酶联免疫法CA15-3诊断试剂盒进行对比检测,其检出率为3.33%,特异度为100%。绘制ROC曲线对比显示,本研究所建立的双抗体夹心ELISA方法对乳腺癌诊断的准确度明显高于CA15-3试剂盒。结论本研究成功建立了特异性强,灵敏度良好的双抗体间接夹心ELISA试剂盒,有望开发为临床辅助诊断的常规试剂盒,尤其有望应用于乳腺癌的大规模筛查及早期诊断。