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Variable density of CD8+ and CD25+ programmed cell death-1 (PD-1) ligand (PD-L1) CD4+ T cells within the tumor microenvironment causes differential responses to the PD-1/PD-L1 blockade

  • Si-Pei Wu
  • Yi-Long Wu
Open Access
Poster presentation
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Keywords

Tumor Microenvironment Peripheral Blood Lymphocyte Variable Density Differential Response Peripheral Blood Sample 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
The programmed cell death-1 (PD-1)/programmed cell death-1 ligand (PD-L1) pathway has been shown to play a pivotal role in tumor evasion. Inhibition of PD-1 and its ligand PD-L1 using an immune checkpoint inhibitor has emerged as a promising immunotherapy for the treatment of various types of cancer. The expression of PD-L1 in tumor cells and tumor-infiltrating lymphocytes (TILs) has been shown to be correlated with improved efficacy of antibodies against PD-1 or PD-L1. Moreover, the density of CD8+ TILs has been shown to be correlated with the response to immunotherapy. In this study, we examined the expression of PD-L1, CD25, PD-1, FoxP3, CD4, CD8, and EpCAM in 42 peripheral blood samples and fresh tumor specimens using multiparametric flow cytometry. Our results showed that the percentages of PD-L1-expressing CD25+ CD4+ T cells were significantly higher in TILs than in peripheral blood lymphocytes (PBLs; TILs: mean, 48.6%; range, 23.6–81.5% versus PBLs: mean, 35.4%; range, 16.8–64.3%; P < 0.001). The density of CD25+ PD-L1+ CD4+ TILs positively correlated with that of PD-1+ CD8+ TILs but negatively correlated with interferon (IFN)-γ+ and tumor necrosis factor (TNF)-β+ CD8+ TILs. However, the high ratio of CD8+ TILs to that of CD25+ PD-L1+ CD4+ TILs or to EpCAM+ tumor cells were associated with high percentages of IFN-γ+ and TNF-β+ CD8+ TILs. Moreover, inhibition of PD-L1 and PD-1 decreased the density of CD25+ PD-L1+ CD4+ cells and PD-1+ CD8+ TILs but increased the percentage of IFN-γ+ and TNF-β+ CD8+ cells. High ratios of CD8+ TILs to CD25+ PD-L1+ CD4+ TILs or to EpCAM+ tumor cells enhanced the activity of tumor-specific CD8+ T cells after PD-1/PD-L1 blockade therapy. Taken together, our results highlighted the importance of CD25+ PD-L1+ CD4+ TILs in mediating the tumor microenvironment immune response. Our findings also indicated that high ratios of CD8+ TILs to CD25+ PD-L1+ CD4+ TILs or to EpCAM+ tumor cells in patients may be more effective after PD-1/PD-L1 blockade therapy. Thus, the variable density of CD8+ and CD25+ PD-L1+ CD4+ T cells within the tumor microenvironment caused differential responses to PD-1/PD-L1 blockade.
Figure 2

Correlation between the clinicopathologic characteristics and PD-1+CD8 TIL or PD-L1+CD4 TIL in 42 lung cancer patients.

Copyright information

© Wu and Wu 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors and Affiliations

  • Si-Pei Wu
    • 1
  • Yi-Long Wu
    • 1
  1. 1.Guangdong General HospitalGuangzhouPeople's Republic China

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