ImMucin: A novel therapeutic vaccine with promiscuous MHC binding for the treatment of MUC1-expressing tumors

Kovjazin, Riva; Volovitz, Ilan; Kundel, Yulia; Rosenbaum, Eli; Medalia, Gal; Horn, Galit; Smorodinsky, Nechama I.; Brenner, Baruch; Carmon, Lior

doi:10.1016/j.vaccine.2011.04.103

Cited by 38 publications

(50 citation statements)

References 69 publications

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“…As we previously identified CD8 ϩ T cell epitopes in the signal peptide, we considered the entire sequence of MDK including the mature form of the protein secreted by tumors and the signal peptide, which remains in the cell (21). Few CD4 ϩ T cell epitopes have been found in signal peptides (22,23), but here, we demonstrate that the MDK signal peptide contains both subdominant and cryptic CD4 ϩ T cell epitopes.…”

Section: Midkine (Mdk)supporting

confidence: 49%

“…To our experience, this peptide induces a substantial T cell response. To our knowledge, few CD4 ϩ T cell epitopes contained in signal peptides have been reported (22,23). They have been delineated in signal peptides of the tumor antigen Muc-1 (23) and the Caf1 antigen of Yersinia pestis (22).…”

Section: Discussionmentioning

confidence: 99%

“…They have been delineated in signal peptides of the tumor antigen Muc-1 (23) and the Caf1 antigen of Yersinia pestis (22). As stated by the authors, BALB/c mice inoculated with metastatic MUC1-transfected murine DA3 mammary tumor cells exhibited significantly prolonged survival following vaccination with MUC1 signal peptide (23). Some HLA-DR1-transgenic mice infected with Y. pestis responded to peptides contained in the signal peptide of Caf1, suggesting that after cleavage from Caf1, the signal sequence is available for antigen presentation during infection (22).…”

Section: Discussionmentioning

confidence: 99%

“…Peptide peptidase has been implicated in the processing of the preprocalcitonin tumor antigen (19). Presentation of the preprocalcitonin [16][17][18][19][20][21][22][23][24][25] ϩ T cell epitope is inhibited by the preincubation of tumor cells with the serine protease inhibitor dichloroisocoumarin. However, in our experiments dichloroisocoumarin was toxic to the A375 melanoma cell line, even a low dose, such that they were uninformative (data not shown).…”

Section: Discussionmentioning

confidence: 99%

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The Signal Peptide of the Tumor-shared Antigen Midkine Hosts CD4+ T Cell Epitopes

Kerzerho¹,

Schneider²,

Favry³

et al. 2013

Journal of Biological Chemistry

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Background: The CD4 T cell response to the tumor antigen Midkine was unknown. Results: Most of the T cell response to Midkine relies on T cell epitopes contained in its signal peptide. Conclusion:The signal peptide of Midkine is accessible to HLA class II pathway for CD4 T cell presentation. Significance: It is a new function for signal peptides to contribute to tumor-specific CD4 T cell response.

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Section: Midkine (Mdk)supporting

confidence: 49%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Signal Peptide of the Tumor-shared Antigen Midkine Hosts CD4+ T Cell Epitopes

Kerzerho¹,

Schneider²,

Favry³

et al. 2013

Journal of Biological Chemistry

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“…Along with others, we have demonstrated the preferred immunogenicity of the signal peptide (SP) domain of MUC1 (8)(9)(10). This short domain has promiscuous binding to multiple major histocompatibility complex (MHC) class I and II, a characteristic that supports its process and presentation on the Autoantibodies against the signal peptide domain of MUC1 in patients with multiple myeloma: Implications for disease diagnosis and prognosis cell surface of various tumor cells and antigen presenting cells (10).…”

Section: Introductionmentioning

confidence: 75%

Autoantibodies against the signal peptide domain of MUC1 in patients with multiple myeloma: Implications for disease diagnosis and prognosis

Kovjazin¹,

Dubnik²,

Horn

et al. 2012

Experimental and Therapeutic Medicine

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pDCs efficiently process synthetic long peptides to induce functional virus‐ and tumour‐specific T‐cell responses

Aspord

Leloup²,

Reche³

et al. 2014

Eur J Immunol

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Keywords: Cancer r Cross-presentation r Long peptides r Plasmacytoid dendritic cells r Viral infectionAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDeveloping efficient therapeutic strategies for cancer and viral infection remains challenging. Successful immunotherapies should elicit robust cell-mediated immunity that is able to eliminate tumour-or virus-infected cells, since strong and multi-specific cytotoxic T lymphocytes (CTLs) responses are often associated with better clinical outcomes in cancer [1] and chronic infectious diseases [2,3]. In the past, the main focus of immunotherapies was on eliciting cytotoxic CD8 + T-cell responses; however, accumulatCorrespondence: Dr. Caroline Aspord e-mail: carolineaspord@yahoo.com ing evidence suggests that CD4 + T cells also play an important role in sustaining immune responses against cancer and infection [4,5]. CD4 + T cells provide critical help to CD8 + T cells, promoting their survival, expansion, and acquisition of effector functions [6,7]. CD4 + T cells also display direct antitumour cytolytic activity [8]. In melanoma, more favourable clinical outcomes are associated with immune responses towards many MHC class I and class II epitopes derived from several tumour antigens [9][10][11]. T-cell immunity, particularly when both CD4 + and CD8 + arms of immunity are involved, has also been shown to protect against cytomegalovirus (CMV) reactivation and disease [12]. Therefore, both CD4 + and CD8 + T cells play a pivotal role in inducing and maintaining therapeutic anti-tumour and anti-viral immunity.C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2014. 44: 2880-2892 Antigen processing As their size prevents a direct binding to MHC class I molecules, SLPs must be taken up and processed before they can be presented to T cells. Such cross-presentation involves dendritic cells (DCs) [21,22], which go on to cross-prime CTL and Th-cell immune responses [23]. Myeloid DCs (mDCs) have already been shown to cross-present SLPs and subsequently induce immune responses [22,24]. Plasmacytoid DCs (pDCs) are another interesting DC subset, also playing a critical role in shaping and regulating immune responses [25,26]. pDCs appear as novel vectors for immunotherapy for both cancer and infections [27][28][29][30], but their ability to cross-present SLP has never been investigated. Nonetheless, there is increasing evidence that pDCs effectively capture, process, and present antigens to T cells [31] Fig. 1C and D). Interestingly, despite some variations depending on the donors used, cross-presentation of long peptides significantly improved with a longer processing time (24 h) with both the pDC line ( Fig. 1E) and primary pDCs (Fig. 1F). To exclude any bystander effects of the peptivator pools, we used three individual long peptides encompassing the cross-presented epitope. All of them were well processed and cross-presented by pDCs (Fig. 2). The pDC line induced a sligh...

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ImMucin: A novel therapeutic vaccine with promiscuous MHC binding for the treatment of MUC1-expressing tumors

Cited by 38 publications

References 69 publications

The Signal Peptide of the Tumor-shared Antigen Midkine Hosts CD4+ T Cell Epitopes

The Signal Peptide of the Tumor-shared Antigen Midkine Hosts CD4+ T Cell Epitopes

Autoantibodies against the signal peptide domain of MUC1 in patients with multiple myeloma: Implications for disease diagnosis and prognosis

pDCs efficiently process synthetic long peptides to induce functional virus‐ and tumour‐specific T‐cell responses

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