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Cancer Therapy: Clinical

BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma

Dennie T. Frederick, Adriano Piris, Alexandria P. Cogdill, Zachary A. Cooper, Cecilia Lezcano, Cristina R. Ferrone, Devarati Mitra, Andrea Boni, Lindsay P. Newton, Chengwen Liu, Weiyi Peng, Ryan J. Sullivan, Donald P. Lawrence, F. Stephen Hodi, Willem W. Overwijk, Gregory Lizée, George F. Murphy, Patrick Hwu, Keith T. Flaherty, David E. Fisher and Jennifer A. Wargo
Dennie T. Frederick
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Adriano Piris
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Alexandria P. Cogdill
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Zachary A. Cooper
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Cecilia Lezcano
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Cristina R. Ferrone
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Devarati Mitra
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Andrea Boni
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Lindsay P. Newton
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Chengwen Liu
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Weiyi Peng
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Ryan J. Sullivan
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Donald P. Lawrence
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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F. Stephen Hodi
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Willem W. Overwijk
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Gregory Lizée
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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George F. Murphy
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Patrick Hwu
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Keith T. Flaherty
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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David E. Fisher
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Jennifer A. Wargo
Divisions of 1Surgical Oncology, 2Medical Oncology, 3Dermatopathology, and 4Dermatology, Massachusetts General Hospital; 5Department of Medical Oncology, Dana-Farber Cancer Institute; 6Division of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts; and 7Department of Melanoma Medical Oncology, Center for Cancer Immunology Research, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
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DOI: 10.1158/1078-0432.CCR-12-1630 Published March 2013
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Abstract

Purpose: To evaluate the effects of BRAF inhibition on the tumor microenvironment in patients with metastatic melanoma.

Experimental Design: Thirty-five biopsies were collected from 16 patients with metastatic melanoma pretreatment (day 0) and at 10 to 14 days after initiation of treatment with either BRAF inhibitor alone (vemurafenib) or BRAF + MEK inhibition (dabrafenib + trametinib) and were also taken at time of progression. Biopsies were analyzed for melanoma antigens, T-cell markers, and immunomodulatory cytokines.

Results: Treatment with either BRAF inhibitor alone or BRAF + MEK inhibitor was associated with an increased expression of melanoma antigens and an increase in CD8+ T-cell infiltrate. This was also associated with a decrease in immunosuppressive cytokines [interleukin (IL)-6 and IL-8] and an increase in markers of T-cell cytotoxicity. Interestingly, expression of exhaustion markers TIM-3 and PD1 and the immunosuppressive ligand PDL1 was increased on treatment. A decrease in melanoma antigen expression and CD8 T-cell infiltrate was noted at time of progression on BRAF inhibitor alone and was reversed with combined BRAF and MEK inhibition.

Conclusions: Together, these data suggest that treatment with BRAF inhibition enhances melanoma antigen expression and facilitates T-cell cytotoxicity and a more favorable tumor microenvironment, providing support for potential synergy of BRAF-targeted therapy and immunotherapy. Interestingly, markers of T-cell exhaustion and the immunosuppressive ligand PDL1 are also increased with BRAF inhibition, further implying that immune checkpoint blockade may be critical in augmenting responses to BRAF-targeted therapy in patients with melanoma. Clin Cancer Res; 19(5); 1225–31. ©2013 AACR.

Footnotes

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

  • Received May 18, 2012.
  • Revision received December 6, 2012.
  • Accepted January 7, 2013.
  • ©2013 American Association for Cancer Research.
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Clinical Cancer Research: 19 (5)
March 2013
Volume 19, Issue 5
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BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma
Dennie T. Frederick, Adriano Piris, Alexandria P. Cogdill, Zachary A. Cooper, Cecilia Lezcano, Cristina R. Ferrone, Devarati Mitra, Andrea Boni, Lindsay P. Newton, Chengwen Liu, Weiyi Peng, Ryan J. Sullivan, Donald P. Lawrence, F. Stephen Hodi, Willem W. Overwijk, Gregory Lizée, George F. Murphy, Patrick Hwu, Keith T. Flaherty, David E. Fisher and Jennifer A. Wargo
Clin Cancer Res March 1 2013 (19) (5) 1225-1231; DOI: 10.1158/1078-0432.CCR-12-1630

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BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma
Dennie T. Frederick, Adriano Piris, Alexandria P. Cogdill, Zachary A. Cooper, Cecilia Lezcano, Cristina R. Ferrone, Devarati Mitra, Andrea Boni, Lindsay P. Newton, Chengwen Liu, Weiyi Peng, Ryan J. Sullivan, Donald P. Lawrence, F. Stephen Hodi, Willem W. Overwijk, Gregory Lizée, George F. Murphy, Patrick Hwu, Keith T. Flaherty, David E. Fisher and Jennifer A. Wargo
Clin Cancer Res March 1 2013 (19) (5) 1225-1231; DOI: 10.1158/1078-0432.CCR-12-1630
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Clinical Cancer Research
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