MUC1-specific immune responses in human MUC1 transgenic mice immunized with various human MUC1 vaccines

Acres, Bruce; Apostolopoulos, Vasso; Balloul, Jean‐Marc; Wreschner, Daniel H.; Xing, Pei‐Xiang; Ali-Hadji, Dahlila; Bizouarne, Nadine; Kiény, Marie Paule; McKenzie, Ian F. C.

doi:10.1007/pl00006677

Cited by 93 publications

(57 citation statements)

References 29 publications

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“…It must be realized that the situation in vivo may be quite different from that in vitro. It is very likely that mice do possess unrestricted CTLs in vivo, but these CTLs may be difficult to detect in vitro and therefore have never been described previously in mice (52)(53)(54)(55)(56)(57). Nevertheless, alterations in MUC1 expression and induction of cellular and humoral immune responses in the MET mice recapitulate what has been described in human cancers.…”

Section: Figurementioning

confidence: 77%

Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred

Mukherjee

Ginardi

Madsen

et al. 2000

The Journal of Immunology

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Pancreatic cancer is a highly aggressive, treatment refractory cancer and is the fourth leading cause of death in the United States. In humans, 90% of pancreatic adenocarcinomas overexpress altered forms of a tumor-specific Ag, mucin 1 (MUC1; an epithelial mucin glycoprotein), which is a potential target for immunotherapy. We have established a clinically relevant animal model for pancreatic cancer by developing a double transgenic mouse model (called MET) that expresses human MUC1 as self molecule and develops spontaneous tumors of the pancreas. These mice exhibit acinar cell dysplasia at birth, which progresses to microadenomas and acinar cell carcinomas. The tumors express large amounts of underglycosylated MUC1 similar to humans. Tumor-bearing MET mice develop low affinity MUC1-specific CTLs that have no effect on the spontaneously occurring pancreatic tumors in vivo. However, adoptive transfer of these CTLs was able to completely eradicate MUC1-expressing injectable tumors in MUC1 transgenic mice, and these mice developed long-term immunity. These CTLs were MHC class I restricted and recognized peptide epitopes in the immunodominant tandem repeat region of MUC1. The MET mice appropriately mimic the human condition and are an excellent model with which to elucidate the native immune responses that develop during tumor progression and to develop effective antitumor vaccine strategies.

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Section: Figurementioning

confidence: 77%

Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred

Mukherjee

Ginardi

Madsen

et al. 2000

The Journal of Immunology

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“…MUC1-specific CTL in the murine model is MHC class I-restricted [23][24][25]. However, in humans, initial reports indicate that coculture of draining lymph node cells from cancer patients with MUC1 + human cancer cell lines expressing different HLA alleles resulted in the induction of MUC1-specific and MHC-unrestricted CTL [26,27].…”

Section: Discussionmentioning

confidence: 99%

Generation and functional assessment of antigen-specific T cells stimulated by fusions of dendritic cells and allogeneic breast cancer cells

Koido

Tanaka

Tajiri

et al. 2007

Vaccine

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We have reported that fusions of patient-derived dendritic cells (DC) and autologous breast cancer cells induce T-cell responses against autologous tumors. However, the preparation of fusion cells requires patient-derived tumor cells, and these are not always available in the clinical setting. In the present study, we explore an alternative approach to constructing DC-breast cancer fusion vaccine by using breast caner-cell lines. DC generated from HLA-A*0201-positive donor were fused to HLA-A*0201 + allogeneic MCF7 breast cancer cells. These fusion cells co-expressed tumor-associated antigens and DC-derived costimulatory and MHC molecules. Both CD4 and CD8 T cells were activated by the fusion cells as demonstrated by the production of IFN-γ. The fusion cells induced strong antigen-specific CTL activity against their parent cells. The lysis of targets was restricted by HLA-A*0201, since killing was blocked by the anti-HLA-A2 mAb. Similar CTL activity against HLA-A*0201-positive targets was induced when T cells were cocultured with fusions of DC and HLA-A*0201-negative allogeneic BT20 breast cancer cells. In addition, administration of T cells stimulated by DC-breast cancer fusion cells regressed seven-day-old tumors and rendered mice free of disease up to 90 days. These results suggest that tumor-cell lines can be used as a fusion partner in the construction of DC-tumor fusion vaccine. Such fusion cells hold promise since they can be used as a vaccine for active immunotherapy or as stimulators to activate and expand T cells for adoptive immunotherapy.

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“…Early efforts to develop MUC1-based cancer vaccines focused on the use of unglycosylated MUC1 tandem repeat peptides of different lengths, conjugated to different carriers and/or administered with an adjuvant (8,(20)(21)(22)(23)(24)(25)(26)(27). In general, these strategies have failed to elicit effective immune responses to MUC1-expressing cancer cells, probably due to the conformational disparities between nonglycosylated vaccine sequences and tumor-expressed, aberrantly glycosylated MUC1 (10)(11)(12).…”

mentioning

confidence: 99%

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

Lakshminarayanan¹,

Thompson

Wolfert

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

278

260

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The mucin MUC1 is typically aberrantly glycosylated by epithelial cancer cells manifested by truncated O-linked saccharides. The resultant glycopeptide epitopes can bind cell surface major histocompatibility complex (MHC) molecules and are susceptible to recognition by cytotoxic T lymphocytes (CTLs), whereas aberrantly glycosylated MUC1 protein on the tumor cell surface can be bound by antibodies to mediate antibody-dependent cell-mediated cytotoxicity (ADCC). Efforts to elicit CTLs and IgG antibodies against cancer-expressed MUC1 have not been successful when nonglycosylated MUC1 sequences were used for vaccination, probably due to conformational dissimilarities. Immunizations with densely glycosylated MUC1 peptides have also been ineffective due to impaired susceptibility to antigen processing. Given the challenges to immuno-target tumor-associated MUC1, we have identified the minimum requirements to consistently induce CTLs and ADCC-mediating antibodies specific for the tumor form of MUC1 resulting in a therapeutic response in a mouse model of mammary cancer. The vaccine is composed of the immunoadjuvant Pam 3 CysSK 4 , a peptide T helper epitope and an aberrantly glycosylated MUC1 peptide. Covalent linkage of the three components was essential for maximum efficacy. The vaccine produced CTLs, which recognized both glycosylated and nonglycosylated peptides, whereas a similar nonglycosylated vaccine gave CTLs which recognized only nonglycosylated peptide. Antibodies elicited by the glycosylated tripartite vaccine were significantly more lytic compared with the unglycosylated control. As a result, immunization with the glycosylated tripartite vaccine was superior in tumor prevention. Besides its own aptness as a clinical target, these studies of MUC1 are likely predictive of a covalent linking strategy applicable to many additional tumor-associated antigens.cancer vaccine | multicomponent | chemical synthesis | Tn antigen

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MUC1-specific immune responses in human MUC1 transgenic mice immunized with various human MUC1 vaccines

Cited by 93 publications

References 29 publications

Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred

Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred

Generation and functional assessment of antigen-specific T cells stimulated by fusions of dendritic cells and allogeneic breast cancer cells

Immune recognition of tumor-associated mucin MUC1 is achieved by a fully synthetic aberrantly glycosylated MUC1 tripartite vaccine

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