Broadening the repertoire of melanoma-associated T-cell epitopes

Thomas Mørch Frøsig, Rikke Birgitte Lyngaa, Özcan Met, Stine Kiaer Larsen, Marco Donia, Inge Marie Svane, Per thor Straten, Sine Reker Hadrup

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Abstract

Immune therapy has provided a significant breakthrough in the treatment of metastatic melanoma. Despite the remarkable clinical efficacy and established involvement of effector CD8 T cells, the knowledge of the exact peptide-MHC complexes recognized by T cells on the tumor cell surface is limited. Many melanoma-associated T-cell epitopes have been described, but this knowledge remains largely restricted to HLA-A2, and we lack understanding of the T-cell recognition in the context of other HLA molecules. We selected six melanoma-associated antigens (MAGE-A3, NY-ESO-1, gp100, Mart1, tyrosinase and TRP-2) that are frequently recognized in patients with the aim of identifying novel T-cell epitopes restricted to HLA-A1, -A3, -A11 and -B7. Using in silico prediction and in vitro confirmation, we identified 127 MHC ligands and analyzed the T-cell responses against these ligands via the MHC multimer-based enrichment of peripheral blood from 39 melanoma patients and 10 healthy donors. To dissect the T-cell reactivity against this large peptide library, we used combinatorial-encoded MHC multimers and observed the T-cell responses against 17 different peptide-MHC complexes in the patient group and four in the healthy donor group. We confirmed the processing and presentation of HLA-A3-restricted T-cell epitopes from tyrosinase (TQYESGSMDK) and gp100 (LIYRRRLMK) and an HLA-A11-restricted T-cell epitope from gp100 (AVGATKVPR) via the cytolytic T-cell recognition of melanoma cell lines and/or K562 cells expressing the appropriate antigen and HLA molecule. We further found T-cell reactivity against two of the identified sequences among tumor-infiltrating lymphocytes from melanoma patients, suggesting a potential clinical relevance of these sequences.
Original languageEnglish
JournalCancer Immunology, Immunotherapy
Volume64
Issue number5
Pages (from-to)609-620
ISSN0340-7004
DOIs
Publication statusPublished - 2015

Keywords

  • T-cell epitope mapping
  • HLA-A2 negative
  • Melanoma
  • MHC multimer
  • Combinatiorial encoding

Cite this

Frøsig, T. M., Lyngaa, R. B., Met, Ö., Larsen, S. K., Donia, M., Svane, I. M., ... Hadrup, S. R. (2015). Broadening the repertoire of melanoma-associated T-cell epitopes. Cancer Immunology, Immunotherapy, 64(5), 609-620. https://doi.org/10.1007/s00262-015-1664-x
Frøsig, Thomas Mørch ; Lyngaa, Rikke Birgitte ; Met, Özcan ; Larsen, Stine Kiaer ; Donia, Marco ; Svane, Inge Marie ; Straten, Per thor ; Hadrup, Sine Reker. / Broadening the repertoire of melanoma-associated T-cell epitopes. In: Cancer Immunology, Immunotherapy. 2015 ; Vol. 64, No. 5. pp. 609-620.
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abstract = "Immune therapy has provided a significant breakthrough in the treatment of metastatic melanoma. Despite the remarkable clinical efficacy and established involvement of effector CD8 T cells, the knowledge of the exact peptide-MHC complexes recognized by T cells on the tumor cell surface is limited. Many melanoma-associated T-cell epitopes have been described, but this knowledge remains largely restricted to HLA-A2, and we lack understanding of the T-cell recognition in the context of other HLA molecules. We selected six melanoma-associated antigens (MAGE-A3, NY-ESO-1, gp100, Mart1, tyrosinase and TRP-2) that are frequently recognized in patients with the aim of identifying novel T-cell epitopes restricted to HLA-A1, -A3, -A11 and -B7. Using in silico prediction and in vitro confirmation, we identified 127 MHC ligands and analyzed the T-cell responses against these ligands via the MHC multimer-based enrichment of peripheral blood from 39 melanoma patients and 10 healthy donors. To dissect the T-cell reactivity against this large peptide library, we used combinatorial-encoded MHC multimers and observed the T-cell responses against 17 different peptide-MHC complexes in the patient group and four in the healthy donor group. We confirmed the processing and presentation of HLA-A3-restricted T-cell epitopes from tyrosinase (TQYESGSMDK) and gp100 (LIYRRRLMK) and an HLA-A11-restricted T-cell epitope from gp100 (AVGATKVPR) via the cytolytic T-cell recognition of melanoma cell lines and/or K562 cells expressing the appropriate antigen and HLA molecule. We further found T-cell reactivity against two of the identified sequences among tumor-infiltrating lymphocytes from melanoma patients, suggesting a potential clinical relevance of these sequences.",
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Frøsig, TM, Lyngaa, RB, Met, Ö, Larsen, SK, Donia, M, Svane, IM, Straten, PT & Hadrup, SR 2015, 'Broadening the repertoire of melanoma-associated T-cell epitopes', Cancer Immunology, Immunotherapy, vol. 64, no. 5, pp. 609-620. https://doi.org/10.1007/s00262-015-1664-x

Broadening the repertoire of melanoma-associated T-cell epitopes. / Frøsig, Thomas Mørch; Lyngaa, Rikke Birgitte; Met, Özcan; Larsen, Stine Kiaer; Donia, Marco; Svane, Inge Marie; Straten, Per thor; Hadrup, Sine Reker.

In: Cancer Immunology, Immunotherapy, Vol. 64, No. 5, 2015, p. 609-620.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Broadening the repertoire of melanoma-associated T-cell epitopes

AU - Frøsig, Thomas Mørch

AU - Lyngaa, Rikke Birgitte

AU - Met, Özcan

AU - Larsen, Stine Kiaer

AU - Donia, Marco

AU - Svane, Inge Marie

AU - Straten, Per thor

AU - Hadrup, Sine Reker

PY - 2015

Y1 - 2015

N2 - Immune therapy has provided a significant breakthrough in the treatment of metastatic melanoma. Despite the remarkable clinical efficacy and established involvement of effector CD8 T cells, the knowledge of the exact peptide-MHC complexes recognized by T cells on the tumor cell surface is limited. Many melanoma-associated T-cell epitopes have been described, but this knowledge remains largely restricted to HLA-A2, and we lack understanding of the T-cell recognition in the context of other HLA molecules. We selected six melanoma-associated antigens (MAGE-A3, NY-ESO-1, gp100, Mart1, tyrosinase and TRP-2) that are frequently recognized in patients with the aim of identifying novel T-cell epitopes restricted to HLA-A1, -A3, -A11 and -B7. Using in silico prediction and in vitro confirmation, we identified 127 MHC ligands and analyzed the T-cell responses against these ligands via the MHC multimer-based enrichment of peripheral blood from 39 melanoma patients and 10 healthy donors. To dissect the T-cell reactivity against this large peptide library, we used combinatorial-encoded MHC multimers and observed the T-cell responses against 17 different peptide-MHC complexes in the patient group and four in the healthy donor group. We confirmed the processing and presentation of HLA-A3-restricted T-cell epitopes from tyrosinase (TQYESGSMDK) and gp100 (LIYRRRLMK) and an HLA-A11-restricted T-cell epitope from gp100 (AVGATKVPR) via the cytolytic T-cell recognition of melanoma cell lines and/or K562 cells expressing the appropriate antigen and HLA molecule. We further found T-cell reactivity against two of the identified sequences among tumor-infiltrating lymphocytes from melanoma patients, suggesting a potential clinical relevance of these sequences.

AB - Immune therapy has provided a significant breakthrough in the treatment of metastatic melanoma. Despite the remarkable clinical efficacy and established involvement of effector CD8 T cells, the knowledge of the exact peptide-MHC complexes recognized by T cells on the tumor cell surface is limited. Many melanoma-associated T-cell epitopes have been described, but this knowledge remains largely restricted to HLA-A2, and we lack understanding of the T-cell recognition in the context of other HLA molecules. We selected six melanoma-associated antigens (MAGE-A3, NY-ESO-1, gp100, Mart1, tyrosinase and TRP-2) that are frequently recognized in patients with the aim of identifying novel T-cell epitopes restricted to HLA-A1, -A3, -A11 and -B7. Using in silico prediction and in vitro confirmation, we identified 127 MHC ligands and analyzed the T-cell responses against these ligands via the MHC multimer-based enrichment of peripheral blood from 39 melanoma patients and 10 healthy donors. To dissect the T-cell reactivity against this large peptide library, we used combinatorial-encoded MHC multimers and observed the T-cell responses against 17 different peptide-MHC complexes in the patient group and four in the healthy donor group. We confirmed the processing and presentation of HLA-A3-restricted T-cell epitopes from tyrosinase (TQYESGSMDK) and gp100 (LIYRRRLMK) and an HLA-A11-restricted T-cell epitope from gp100 (AVGATKVPR) via the cytolytic T-cell recognition of melanoma cell lines and/or K562 cells expressing the appropriate antigen and HLA molecule. We further found T-cell reactivity against two of the identified sequences among tumor-infiltrating lymphocytes from melanoma patients, suggesting a potential clinical relevance of these sequences.

KW - T-cell epitope mapping

KW - HLA-A2 negative

KW - Melanoma

KW - MHC multimer

KW - Combinatiorial encoding

U2 - 10.1007/s00262-015-1664-x

DO - 10.1007/s00262-015-1664-x

M3 - Journal article

VL - 64

SP - 609

EP - 620

JO - Cancer Immunology, Immunotherapy

JF - Cancer Immunology, Immunotherapy

SN - 0340-7004

IS - 5

ER -