Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
    • CME
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Breast Cancer
      • Clinical Trials
      • Immunotherapy: Facts and Hopes
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Clinical Cancer Research
Clinical Cancer Research
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
    • Reviewing
    • CME
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Breast Cancer
      • Clinical Trials
      • Immunotherapy: Facts and Hopes
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
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
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1078-0432.CCR-12-1630 Published March 2013
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Article Figures & Data

Figures

  • Additional Files
  • Figure 1.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 1.

    BRAF inhibition is associated with increased melanoma antigen expression in tumors of patients with metastatic melanoma. Tumors were harvested and mRNA levels of gp100, MART-1, TYRP-1, and TYRP-2 in patients with metastatic melanoma undergoing treatment with a selective inhibitor of BRAFV600E were assayed. A, expression levels of the respective MDAs are shown as fold increase over pretreatment value and are plotted on a log scale in a box and whiskers plot (n = 12). The bottom and top of the 25th and 75th percentile, respectively, for all patients, with the bar indicating the median value. The whiskers indicate the extremes with open circles representing data points greater than 1.5 times the interquartile range. Immunohistochemistry (B; ×40 magnification) and immunofluorescence (C) staining for the melanoma antigen MART-1 in pretreatment and on-treatment biopsies (patient 2) was conducted to confirm that protein expression correlated with mRNA expression. All microscopy was repeated at least 3 times with representative examples shown. P values are from a 2-tailed Student t test with a μ of 1, which corresponds to no change in mRNA levels on treatment. *, P ≤ 0.05.

  • Figure 2.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 2.

    BRAF inhibition is associated with increased CD8+ T-cell infiltrate in tumors of patients with metastatic melanoma. Tumors biopsied pretreatment and on-treatment were stained for H&E and immunohistochemistry (IHC) was conducted for CD8+ T cells with a representative patient shown (A). CD8+ T-cell counts were conducted in a blinded fashion by a dedicated dermatopathologist (B). Average CD8+ T-cell counts are plotted for each patient with error bars representing the standard deviation of four measurements. CD8+ counts from all patients (n = 11) are expressed in a box and whiskers plot both pre- and on-treatment (C).

  • Figure 3.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 3.

    BRAF inhibition is associated with decreased immunosuppressive cytokines and markers of T-cell cytotoxicity but increased T-cell exhaustion markers and PDL1 in tumors of patients with metastatic melanoma. Tumors were harvested and mRNA levels of IL-6, IL-8, IL-10, and TGF-β (A), perforin (n = 11), GranzymeB (n = 11), TIM-3 (n = 14) and PD1 (n = 14; B), and PDL1 (n = 11; C) in patients with metastatic melanoma undergoing treatment with a selective inhibitor of BRAFV600E were assayed. All patients are expressed in a box and whiskers plot. Open circles represent data points greater than 1.5 times the interquartile range. P values indicated are from a 2-tailed Student t test with a μ of 1, which represents no change in mRNA value with respect to the pretreatment value. *, P ≤ 0.05. Immunohistochemistry (×40 magnification) for the perforin, GranzymeB, and TIM-3 (patient 6; D) and PDL1 (patient 12; E) in pretreatment and on-treatment biopsies was conducted to confirm that protein expression correlated with mRNA expression. The dotted line = tumor–stroma interface and the inset is the isotype-specific control.

  • Figure 4.
    • Download figure
    • Open in new tab
    • Download powerpoint
    Figure 4.

    Melanoma antigen expression and CD8+ T-cell infiltrate are decreased at time of progression and restored through MEK inhibition. A, tumors were harvested at time of progression and at time of treatment with combined BRAF inhibition and MEK inhibition for patient 3. mRNA levels of the melanoma antigens gp100, MART-1, TYRP-1, and TYRP-2 were assayed. B, immunohistochemistry (IHC) was conducted for CD8+ T cells on patient tumor samples. C, CD8+ T cells were identified and counted by a dedicated pathologist. Average CD8+ T-cell counts are plotted with error bars representing the SD of 4 measurements. *, P ≤ 0.05.

Additional Files

  • Figures
  • Supplementary Data

    Files in this Data Supplement:

    • Supplementary Figure Legend - PDF file - 69K
    • Supplementary Figure 1 - PDF file - 112K, Inhibition of BRAFV600E increases expression of MART-1 in tumors of patients with metastatic melanoma.
    • Supplementary Figure 2 - PDF file - 349K, Inhibition of BRAFV600E is not associated with a significant increase in HLA expression in patients with metastatic melanoma.
    • Supplementary Figure 3 - PDF file - 19K, Melanoma antigen expression is decreased at time of progression.
    • Supplementary Table 1 - PDF file - 50K, Patient Characteristics.
    • Supplementary Table 2 - PDF file - 30K, Inhibition of BRAFV600E increases expression of MDAs in tumors of patients with metastatic melanoma.
PreviousNext
Back to top
Clinical Cancer Research: 19 (5)
March 2013
Volume 19, Issue 5
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Clinical Cancer Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
BRAF Inhibition Is Associated with Enhanced Melanoma Antigen Expression and a More Favorable Tumor Microenvironment in Patients with Metastatic Melanoma
(Your Name) has forwarded a page to you from Clinical Cancer Research
(Your Name) thought you would be interested in this article in Clinical Cancer Research.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
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

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
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
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Disclosure of Potential Conflicts of Interest
    • Authors' Contributions
    • Grant Support
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • Biomarker Analysis from the BERIL-1 Study
  • Radiation and TGFβ Blockade in Metastatic Breast Cancer
  • DAF Inhibition in Metastatic Colorectal Cancer
Show more Cancer Therapy: Clinical
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • CCR Focus Archive
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Clinical Cancer Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Clinical Cancer Research
eISSN: 1557-3265
ISSN: 1078-0432

Advertisement