Impaired T cell function in malignant pleural effusion is caused by TGF-β derived predominantly from macrophages

Lifeng Li, Li Yang, Liping Wang*, Fei Wang, Zhen Zhang, Jieyao Li, Dongli Yue, Xinfeng Chen, Yu Ping, Lan Huang, Bin Zhang, Yi Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Malignant pleural effusion (MPE) is an indication of advanced cancer. Immune dysfunction often occurs in MPE. We aimed to identify the reason for impaired T cell activity in MPE from lung cancer patients and to provide clues toward potential immune therapies for MPE. The surface inhibitory molecules and cytotoxic activity of T cells in MPE and peripheral blood (PB) were analyzed using flow cytometry. Levels of inflammatory cytokines in MPE and PB were tested using ELISA. TGF-β expression in tumor-associated macrophages (TAMs) was also analyzed. The effect of TAMs on T cells was verified in vitro. Lastly, changes in T cells were evaluated following treatment with anti-TGF-β antibody. We found that expression levels of Tim-3, PD-1 and CTLA-4 in T cells from MPE were upregulated compared with those from PB, but levels of IFN-γ and Granzyme B were downregulated (p < 0.05). The amount of TGF-β was significantly higher in MPE than in PB (p < 0.05). TGF-β was mainly produced by TAMs in MPE. When T cells were co-cultured with TAMs, expression levels of Tim-3, PD-1 and CTLA-4 were significantly higher than controls, whereas levels of IFN-γ and Granzyme B were significantly decreased, in a dose-dependent manner (p < 0.05). In vitro treatment with anti-TGF-β antibody restored the impaired T cell cytotoxic activity in MPE. Our results indicate that macrophage-derived TGF-β plays an important role in impaired T cell cytotoxicity. It will therefore be valuable to develop therapeutic strategies against TGF-β pathway for MPE therapy of lung cancer.

Original languageEnglish (US)
Pages (from-to)2261-2269
Number of pages9
JournalInternational Journal of Cancer
Volume139
Issue number10
DOIs
StatePublished - Nov 15 2016

Keywords

  • CD4+ T cells
  • CD8+ T cells
  • TGF-β
  • impaired T cell function
  • malignant pleural effusion (MPE)
  • tumor-associated macrophages (TAMs)

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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