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Reversal of NK-Cell Exhaustion in Advanced Melanoma by Tim-3 Blockade

Ines Pires da Silva, Anne Gallois, Sonia Jimenez-Baranda, Shaukat Khan, Ana C. Anderson, Vijay K. Kuchroo, Iman Osman and Nina Bhardwaj
Ines Pires da Silva
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
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Anne Gallois
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
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Sonia Jimenez-Baranda
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
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Shaukat Khan
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
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Ana C. Anderson
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
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Vijay K. Kuchroo
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
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Iman Osman
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
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Nina Bhardwaj
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
1Cancer Institute; 2The Ronald O. Perelman Department of Dermatology, New York University Langone Medical Center; 3Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine; 4Icahn School of Medicine at Mount Sinai, New York, New York; 5Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; 6Instituto Português de Oncologia de Lisboa Francisco Gentil; and 7Programme for Advanced Medical Education, Lisbon, Portugal
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DOI: 10.1158/2326-6066.CIR-13-0171 Published May 2014
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Abstract

The immunoregulatory protein T-cell immunoglobulin- and mucin-domain–containing molecule-3 (Tim-3) mediates T-cell exhaustion and contributes to the suppression of immune responses in both viral infections and tumors. Tim-3 blockade reverses the exhausted phenotype of CD4+ and CD8+ T cells in several chronic diseases, including melanoma. Interestingly, natural killer (NK) cells constitutively express Tim-3; however, the role of Tim-3 in modulating the function of these innate effector cells remains unclear, particularly in human diseases. In this study, we compared the function of Tim-3 in NK cells from healthy donors and patients with metastatic melanoma. NK cells from the latter were functionally impaired/exhausted, and Tim-3 blockade reversed this exhausted phenotype. Moreover, Tim-3 expression levels were correlated with the stage of the disease and poor prognostic factors. These data indicate that Tim-3 can function as an NK-cell exhaustion marker in advanced melanoma and support the development of Tim-3–targeted therapies to restore antitumor immunity. Cancer Immunol Res; 2(5); 410–22. ©2014 AACR.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Received September 30, 2013.
  • Revision received January 22, 2014.
  • Accepted January 27, 2014.
  • ©2014 American Association for Cancer Research.
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Cancer Immunology Research: 2 (5)
May 2014
Volume 2, Issue 5
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Reversal of NK-Cell Exhaustion in Advanced Melanoma by Tim-3 Blockade
Ines Pires da Silva, Anne Gallois, Sonia Jimenez-Baranda, Shaukat Khan, Ana C. Anderson, Vijay K. Kuchroo, Iman Osman and Nina Bhardwaj
Cancer Immunol Res May 1 2014 (2) (5) 410-422; DOI: 10.1158/2326-6066.CIR-13-0171

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Reversal of NK-Cell Exhaustion in Advanced Melanoma by Tim-3 Blockade
Ines Pires da Silva, Anne Gallois, Sonia Jimenez-Baranda, Shaukat Khan, Ana C. Anderson, Vijay K. Kuchroo, Iman Osman and Nina Bhardwaj
Cancer Immunol Res May 1 2014 (2) (5) 410-422; DOI: 10.1158/2326-6066.CIR-13-0171
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