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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.
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Research Article Immunology

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

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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

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Figure 1

CD8+ TILs exhibit unique phenotypic traits compared with PBLs.

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CD8+ TILs exhibit unique phenotypic traits compared with PBLs.
 
(A) Phe...
(A) Phenotypic characterization of CD8+ PBLs and TILs in melanoma patients. Percentages of PBLs and TILs expressing individual or combination of markers are shown (mean ± SEM). Each dot represents 1 sample analyzed. **P < 0.01, ***P < 0.001, Mann-Whitney test. (B) Coexpression of PD-1, LAG-3, TIM-3, and 4-1BB in CD8+ PBLs and TILs. The frequency of cells expressing 0, 1, 2, 3, or 4 markers is shown. Bars represent maximum, minimum, and mean values. **P < 0.01, ***P < 0.001, Mann-Whitney test. (C) Coexpression pattern of PD-1 and LAG-3, TIM-3, 4-1BB, CD27, and CD57 on CD8+ PBLs and TILs. Dot plots display the phenotype of CD8+ lymphocytes from matched samples from 1 representative patient. The percentage of cells expressing each combination of receptors is shown. (D) Frequency of PD-1 expression on CD8+ TIL subpopulations. TIM-3+, LAG-3+, 4-1BB+, CD25+, BTLA+, CD57+, and CD27+ CD8+ TILs were gated, and the frequency of PD-1 expression within these populations is summarized. Markers are displayed in order and color coded according to frequency of PD-1 expression. Mean ± SEM are shown. *P < 0.005 vs. BTLA+, CD57+, and CD27+, Dunn test for multiple comparisons.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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