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Identification of a naturally processed HLA-A*02:01-restricted CTL epitope from the human tumor-associated antigen Nectin-4

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Abstract

Nectin-4 is a tumor antigen present on the surface of breast, ovarian and lung carcinoma cells. It is rarely present in normal adult tissues and is therefore a candidate target for cancer immunotherapy. Here, we identified a Nectin-4 antigenic peptide that is naturally presented to T cells by HLA-A2 molecules. We first screened the 502 nonamer peptides of Nectin-4 (510 amino acids) for binding to and off-rate from eight different HLA class I molecules. We then combined biochemical, cellular and algorithmic assays to select 5 Nectin-4 peptides that bound to HLA-A*02:01 molecules. Cytolytic T lymphocytes were obtained from healthy donors, that specifically lyzed HLA-A2+ cells pulsed with 2 out of the 5 peptides, indicating the presence of anti-Nectin-4 CD8+ T lymphocytes in the human T cell repertoire. Finally, an HLA-A2-restricted cytolytic T cell clone derived from a breast cancer patient recognized peptide Nectin-4145–153 (VLVPPLPSL) and lyzed HLA-A2+ Nectin-4+ breast carcinoma cells. These results indicate that peptide Nectin-4145–153 is naturally processed for recognition by T cells on HLA-A2 molecules. It could be used to monitor antitumor T cell responses or to immunize breast cancer patients.

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Abbreviations

CTL:

Cytolytic T lymphocyte

EBV:

Epstein–Barr virus

EBV-B:

B cells transformed by the Epstein–Barr virus

ERBB2:

Erb-B2 receptor tyrosine kinase 2

GnT-V:

N-acetylglucosaminyltransferase V

HER2:

Human epidermal growth factor receptor 2

MAGEA3:

Melanoma antigen family A3

MAGEA10:

Melanoma antigen family A10

MAGEC2:

Melanoma antigen family C2

MFI:

Mean fluorescence intensity

MUC1:

Mucin 1

NY-ESO-1:

New York esophageal squamous cell carcinoma 1

PRAME:

Preferentially expressed antigen in melanoma

PVRL4:

Poliovirus receptor-related 4

TAP:

Transporter associated with antigen processing

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Acknowledgments

This work was supported by grants from INSERM, Institut Paoli-Calmettes, Ligue Nationale Contre le Cancer, Institut National du Cancer (AO projet libre, 2008–2010), and Fondation contre le Cancer (Brussels, Belgium).

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Authors and Affiliations

  1. Inserm U1068, Centre de Recherche en Cancérologie de Marseille (CRCM), Equipe Oncologie Moléculaire, UM 105, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France

    Marc Lopez

  2. Inserm U1068, Centre de Recherche en Cancérologie de Marseille (CRCM), Equipe Immunité et Cancer, UM 105, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, 27 bd Lei Roure, 13009, Marseille, France

    Abderrezak Ghidouche, Caroline Rochas & Daniel Olive

  3. Ludwig Institute for Cancer Research, Brussels Branch, Brussels, Belgium

    Danièle Godelaine & Didier Colau

  4. de Duve Institute, Université catholique de Louvain, Brussels, Belgium

    Danièle Godelaine, Didier Colau, Gérald Hames & Pierre G. Coulie

  5. Department of Oncology and Hematology, Grand Hôpital de Charleroi, Charleroi, Belgium

    Javier Carrasco

  6. bioMérieux Industry, Ivry sur Seine, France

    Félix A. Montero-Julian

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  1. Marc Lopez
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  2. Abderrezak Ghidouche
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  3. Caroline Rochas
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  4. Danièle Godelaine
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Correspondence to Daniel Olive.

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Lopez, M., Ghidouche, A., Rochas, C. et al. Identification of a naturally processed HLA-A*02:01-restricted CTL epitope from the human tumor-associated antigen Nectin-4. Cancer Immunol Immunother 65, 1177–1188 (2016). https://doi.org/10.1007/s00262-016-1877-7

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