Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Tumor-infiltrating BRAFV600E-specific CD4+ T cells correlated with complete clinical response in melanoma
Joshua R. Veatch, … , William W. Kwok, Stanley R. Riddell
Joshua R. Veatch, … , William W. Kwok, Stanley R. Riddell
Published January 23, 2018
Citation Information: J Clin Invest. 2018;128(4):1563-1568. https://doi.org/10.1172/JCI98689.
View: Text | PDF
Concise Communication Immunology Oncology

Tumor-infiltrating BRAFV600E-specific CD4+ T cells correlated with complete clinical response in melanoma

  • Text
  • PDF
Abstract

T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Unfortunately, most neoantigens result from random mutations and are patient specific, and some cancers contain few mutations to serve as potential antigens. We describe a patient with stage IV acral melanoma who achieved a complete response following adoptive transfer of tumor-infiltrating lymphocytes (TILs). Tumor exome sequencing surprisingly revealed fewer than 30 nonsynonymous somatic mutations, including oncogenic BRAFV600E. Analysis of the specificity of TILs identified rare CD4+ T cells specific for BRAFV600E and diverse CD8+ T cells reactive to nonmutated self-antigens. These specificities increased in blood after TIL transfer and persisted long-term, suggesting they contributed to the effective antitumor immune response. Gene transfer of the BRAFV600E-specific T cell receptor (TCR) conferred recognition of class II MHC–positive cells expressing the BRAF mutation. Therapy with TCR-engineered BRAFV600E-specific CD4+ T cells may have direct antitumor effects and augment CD8+ T cell responses to self- and/or mutated tumor antigens in patients with BRAF-mutated cancers.

Authors

Joshua R. Veatch, Sylvia M. Lee, Matthew Fitzgibbon, I-Ting Chow, Brenda Jesernig, Tom Schmitt, Ying Ying Kong, Julia Kargl, A. McGarry Houghton, John A. Thompson, Martin McIntosh, William W. Kwok, Stanley R. Riddell

×

Figure 1

CD4+ T cells specific for BRAFV600E isolated from post–TIL infusion PBMCs are restricted by HLA DQB1*03.

Options: View larger image (or click on image) Download as PowerPoint
CD4+ T cells specific for BRAFV600E isolated from post–TIL infusion PBMC...
(A) Positron emission tomography showing recurrent tumor in left iliac region (left) and left thigh (right). (B–D) Specificity and HLA restriction of BRAFV600E-specific T cells. (B) IFN-γ production by a patient-derived T cell line incubated with autologous B cells pulsed with WT and mutant BRAF peptide. (C) Recognition of autologous B cells transfected with mRNA encoding mutant or WT BRAF sequences. (D) Recognition of autologous B cells pulsed with mutated BRAF peptide in the presence or absence of HLA blocking antibodies. (E) BRAF-specific CD4+ T cell recognition of the B-LCL line 1331 (DR0404, DQA1*0301/DQB1*0302), which is matched at HLA-DQ with the patient, and the HLA-DQ-mismatched B-LCL line VAVY (DR3, DQA1*0501/DQB1*0201) prior to and after transduction with HLA-DRB1*0404 (DR4) or HLA-DQB1*0302/DQA1*0301 (DQ8). Assays were performed with and without pulsing with BRAFV600E peptide. Experiments were performed with 2–3 technical replicates.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts