Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

Creaney, Jenette; Segal, Amanda; Sterrett, Gregory F.; Platten, Michael; Baker, Elizabeth; Murch, Ashleigh; Nowak, Anna K.; Robinson, B. W.; Millward, Michael

doi:10.1038/sj.bjc.6604340

Cited by 44 publications

(24 citation statements)

References 30 publications

(24 reference statements)

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“…Our study suggests that cross-presentation of membrane-localized tumor antigens might represent a more complex system involving both LNresident and migratory DC subsets. This is important for tumor because in humans, several membrane associated tumor molecules have been shown to be antigenic, including gp100, tyrosinase, MUC-1 and carcinoembryonic antigen in melanoma, mesothelioma, and ovarian cancer, respectively [36][37][38]. Importantly, CD8 1 T cells specific for membrane-associated tumor antigens can be detected within sentinel LN and circulating in peripheral blood [39,40].…”

mentioning

confidence: 99%

CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

et al. 2010

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One of the clear paradoxes in tumor immunology is the fact that cross-presentation of cellassociated tumor antigens to CD8 1 T cells is efficient, yet CTL generation is weak, and tumors continue to grow. We examined, for the first time whether this may be due to alterations in the phenotype or function of cross-presenting DC using a solid tumor model expressing a membrane bound neo-antigen (hemagglutinin, HA). Tumor antigen was constitutively cross-presented in the tumor-draining LN throughout tumor progression by CD11c 1 DC. Further analysis revealed that both CD8a 1 and CD8a À DC subsets, but not plasmacytoid DC, were effective at cross-presenting HA tumor antigen. The proportions of DC subsets in the tumor-draining LN were equivalent to those seen in the LN of naïve mice; however, a significant increase in the expression of the potential inhibitory B7 molecule, B7-DC, was noted and appeared to be restricted to the CD8a -DC subset. Therefore LN resident CD8a 1 DC are not the sole DC subset capable of cross-presenting cell-associated tumor antigens. Migratory tumor DC subsets with altered co-stimulatory receptor expression may contribute to induction and regulation of tumor-specific responses.Key words: Cross-presentation . DC . Membrane antigen . Tumor immunology IntroductionWe have shown in previous studies that cell-associated tumor antigens are cross-presented by host APC to CD8 1 T cells [1][2][3].Despite efficient cross presentation of tumor antigens, only a weak, localized CTL response is induced and this response fails to control tumor growth [1,3,4]. Similarly in patients with cancer, tumor specific CD8 1 T cells, induced spontaneously or in response to therapy, are often detected in the tumor tissue, local draining LN and peripheral blood of cancer patients, without the induction of tumor regression [5,6]. This failure to generate strong CTL responses despite the presentation of the appropriate tumor antigen is perplexing. This lack of an effective anti-tumor CTL response is likely related to the way in which tumor antigens are presented by DC.Evidence from the field of virology, where CTL play a crucial role in controlling viral infection, demonstrates that generation of an effective CTL response requires presentation of viral antigens by activated APC, specifically DC. Notably, in this regard, cancer is generally associated with an environment that does not favor DC activation, indeed, DC found in tumor tissue and local tumordraining LN (TDLN) of cancer patients and tumor-bearing animals display a non-activated phenotype [7,8]. Thus, the manner in which tumor antigens are presented to the immune system, particularly by cross-presenting DC, may be vital in shaping the nature of tumor-specific CD8 1 T-cell responses.Though the contribution of cross-presentation to the generation of anti-tumor immunity has been challenged [9,10], there is convincing evidence that tumor antigens are efficiently crosspresented in vivo [1,[11][12][13]. DC are thought to be the principal cell type responsible for antigen c...

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CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

et al. 2010

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“…It is overexpressed in the majority of epithelioid MM in an altered glycosylation form (Creaney et al, 2008). While it has been shown that Muc-1 + MM cells are subject to CTL-mediated killing in vitro (Roulois et al, 2011), there are currently no Muc-1 targeted therapies under development for MM patients.…”

Section: Tumour-associated Antigens In MMmentioning

confidence: 99%

The Role of Immunotherapy in the Treatment of Mesothelioma

Al-Taei¹,

Lester²,

Tabi³

2012

Mesotheliomas - Synonyms and Definition, Epidemiology, Etiology, Pathogenesis, Cyto-Histopathological Features, Clinic, Diagnos

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“…To date, it is known that MUC1 is overexpressed by MPM cells compared with normal mesothelioma cells [23]. Thus, MUC1 could represent an attractive TAA to target CTL responses against MPM.…”

Section: Alignant Pleural Mesothelioma (Mpm)mentioning

confidence: 99%

Recognition of pleural mesothelioma by mucin-1(950-958)/human leukocyte antigen A*0201-specific CD8+ T-cells

Roulois

Vignard

Gueugnon

et al. 2011

European Respiratory Journal

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Recent clinical investigations have demonstrated that T-cell-based immunotherapy of malignant pleural mesothelioma (MPM) could represent an alternative to the other therapeutic strategies. However, its development suffers from the lack of identified tumour antigenic targets. Mucin (MUC)1, which is expressed and recognised by cytotoxic T-cells in numerous cancer types, has not been investigated as a potential immune target in MPM. Thus, the objective of this study was to analyse MUC1 expression by MPM cells and to determine whether this antigen can be the target of cytotoxic CD8+ T-cells (cytotoxic T-lymphocytes (CTLs)).We first evaluated the expression and glycosylation of MUC1 by MPM cell lines using different MUC1-specific monoclonal antibodies. We then obtained a CTL clone specific for a MUC1 peptide (residues 950-958) presented by human leukocyte antigen (HLA)-A*0201 and studied its interferon-c and cytotoxic response to MPM cell lines.We found that all MPM cell lines expressed MUC1 protein at the cell surface with different glycosylation profiles. We also observed that HLA-A*0201+ MPM cell lines are recognised and lysed by a HLA-A*0201/MUC1(950-958)-specific CTL clone independently of the MUC1 glycosylation profile.Thus, MUC1 expression and antigen presentation by MPM cells may represent an attractive target for immunotherapeutic treatment of MPM despite its hyperglycosylated profile.

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Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

Cited by 44 publications

References 30 publications

CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

The Role of Immunotherapy in the Treatment of Mesothelioma

Recognition of pleural mesothelioma by mucin-1(950-958)/human leukocyte antigen A*0201-specific CD8+ T-cells

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Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

Cited by 44 publications

References 30 publications

CD8α+ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

CD8α+ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

The Role of Immunotherapy in the Treatment of Mesothelioma

Recognition of pleural mesothelioma by mucin-1(950-958)/human leukocyte antigen A*0201-specific CD8+ T-cells

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CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor

CD8α⁺ DC are not the sole subset cross‐presenting cell‐associated tumor antigens from a solid tumor