Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • 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
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Next-Generation Sequencing in Medicine (Upcoming)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • Gut-Brain Axis (Jul 2021)
    • Tumor Microenvironment (Mar 2021)
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors
Alena Gros, … , James C. Yang, Steven A. Rosenberg
Alena Gros, … , James C. Yang, Steven A. Rosenberg
Published March 25, 2014
Citation Information: J Clin Invest. 2014;124(5):2246-2259. https://doi.org/10.1172/JCI73639.
View: Text | PDF
Research Article Immunology

PD-1 identifies the patient-specific CD8+ tumor-reactive repertoire infiltrating human tumors

  • Text
  • PDF
Abstract

Adoptive transfer of tumor-infiltrating lymphocytes (TILs) can mediate regression of metastatic melanoma; however, TILs are a heterogeneous population, and there are no effective markers to specifically identify and select the repertoire of tumor-reactive and mutation-specific CD8+ lymphocytes. The lack of biomarkers limits the ability to study these cells and develop strategies to enhance clinical efficacy and extend this therapy to other malignancies. Here, we evaluated unique phenotypic traits of CD8+ TILs and TCR β chain (TCRβ) clonotypic frequency in melanoma tumors to identify patient-specific repertoires of tumor-reactive CD8+ lymphocytes. In all 6 tumors studied, expression of the inhibitory receptors programmed cell death 1 (PD-1; also known as CD279), lymphocyte-activation gene 3 (LAG-3; also known as CD223), and T cell immunoglobulin and mucin domain 3 (TIM-3) on CD8+ TILs identified the autologous tumor-reactive repertoire, including mutated neoantigen-specific CD8+ lymphocytes, whereas only a fraction of the tumor-reactive population expressed the costimulatory receptor 4-1BB (also known as CD137). TCRβ deep sequencing revealed oligoclonal expansion of specific TCRβ clonotypes in CD8+PD-1+ compared with CD8+PD-1– TIL populations. Furthermore, the most highly expanded TCRβ clonotypes in the CD8+ and the CD8+PD-1+ populations recognized the autologous tumor and included clonotypes targeting mutated antigens. Thus, in addition to the well-documented negative regulatory role of PD-1 in T cells, our findings demonstrate that PD-1 expression on CD8+ TILs also accurately identifies the repertoire of clonally expanded tumor-reactive cells and reveal a dual importance of PD-1 expression in the tumor microenvironment.

Authors

Alena Gros, Paul F. Robbins, Xin Yao, Yong F. Li, Simon Turcotte, Eric Tran, John R. Wunderlich, Arnold Mixon, Shawn Farid, Mark E. Dudley, Ken-ichi Hanada, Jorge R. Almeida, Sam Darko, Daniel C. Douek, James C. Yang, Steven A. Rosenberg

×

Figure 4

PD-1+, LAG-3+, and TIM-3+ derived CD8+ TILs prospectively identify tumor-reactive CD8+ TILs targeting a mutation in the CDKN2A gene locus.

Options: View larger image (or click on image) Download as PowerPoint
PD-1+, LAG-3+, and TIM-3+ derived CD8+ TILs prospectively identify tumor...
CD3+CD8+ TILs were sorted to high purity from FrTu1913 based on positive or negative expression of PD-1, LAG-3, and TIM-3 and expanded in vitro. (A) Recognition of CDKN2Amut peptide pulsed COS-A11 cells by PD-1+ and PD-1– TILs. TILs were cocultured with COS-A11 cells pulsed with an irrelevant A*1101 restricted peptide, with CDKN2Amut peptide (1 μM), or with plate-bound anti-CD3. Dot plots display the frequency of expression of 4-1BB and CDKN2Amut peptide HLA-A*1101 tetramer complex binding of PD-1– (left) and PD-1+ (right) derived CD8+ TILs 24 hours after coculture. (B) IFN-γ secretion and frequency of CDKN2Amut tetramer+ cells in FrTu1913-derived TILs. TILs derived from FrTu1913 and control TIL3309, recognizing CRKRSmut HLA-A*1101 peptide, were cocultured with COS-A11 alone or pulsed with specific or irrelevant peptides; mean secretion of IFN-γ (duplicates) is represented. The frequency of CDKN2Amut-specific cells in the TIL populations was determined using a CDKN2Amut peptide HLA-A*1101 tetramer complex after gating on CD3+CD8+ cells (gray bars).

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts