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Identification and characterization of agonist epitopes of the MUC1-C oncoprotein

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Abstract

The MUC1 tumor-associated antigen is overexpressed in the majority of human carcinomas and several hematologic malignancies. Much attention has been paid to the hypoglycosylated variable number of tandem repeats (VNTR) region of the N-terminus of MUC1 as a vaccine target, and recombinant viral vector vaccines are also being evaluated that express the entire MUC1 transgene. While previous studies have described MUC1 as a tumor-associated tissue differentiation antigen, studies have now determined that the C-terminus of MUC1 (MUC1-C) is an oncoprotein, and its expression is an indication of poor prognosis in numerous tumor types. We report here the identification of nine potential CD8+ cytotoxic T lymphocyte epitopes of MUC1, seven in the C-terminus and two in the VNTR region, and have identified enhancer agonist peptides for each of these epitopes. These epitopes span HLA-A2, HLA-A3, and HLA-A24 major histocompatibility complex (MHC) class I alleles, which encompass the majority of the population. The agonist peptides, compared to the native peptides, more efficiently (a) generate T-cell lines from the peripheral blood mononuclear cells of cancer patients, (b) enhance the production of IFN-γ by peptide-activated human T cells, and (c) lyse human tumor cell targets in an MHC-restricted manner. The agonist epitopes described here can be incorporated into various vaccine platforms and for the ex vivo generation of human T cells. These studies provide the rationale for the T-cell-mediated targeting of the oncogenic MUC1-C, which has been shown to be an important factor in both drug resistance and poor prognosis for numerous tumor types.

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Abbreviations

APC:

Antigen-presenting cell

CTL:

Cytotoxic T lymphocyte

DC:

Dendritic cell

EGFR:

Epidermal growth factor receptor

EMT:

Epithelial to mesenchymal transition

HLA:

Human leukocyte antigen

IVS:

In vitro stimulation

MHC:

Major histocompatibility complex

MUC1-C:

C-terminal region of MUC1

MUC1-N:

N-terminal region of MUC1

OS:

Overall survival

PBMC:

Peripheral blood mononuclear cell

TAA:

Tumor-associated antigen

TTP:

Time to progression

VNTR:

Variable number of tandem repeats

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Acknowledgments

Grant support was provided by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. The authors thank Diane J. Poole for technical assistance and Debra Weingarten for editorial assistance in the preparation of this manuscript.

Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, MSC 1750, Bethesda, MD, 20892, USA

    Caroline Jochems, Jo A. Tucker, Matteo Vergati, Benjamin Boyerinas, James L. Gulley, Jeffrey Schlom & Kwong-Yok Tsang

  2. Medical Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    James L. Gulley

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  1. Caroline Jochems
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  2. Jo A. Tucker
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Correspondence to Jeffrey Schlom.

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J. Schlom and K.-Y. Tsang contributed equally to this paper.

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Jochems, C., Tucker, J.A., Vergati, M. et al. Identification and characterization of agonist epitopes of the MUC1-C oncoprotein. Cancer Immunol Immunother 63, 161–174 (2014). https://doi.org/10.1007/s00262-013-1494-7

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