Depletion of CD4+ CD25+ regulatory T cells promotes CCL21-mediated antitumor immunity

PLoS One. 2013 Sep 2;8(9):e73952. doi: 10.1371/journal.pone.0073952. eCollection 2013.

Abstract

CCL21 is known to attract dendritic cells (DCs) and T cells that may reverse tumor-mediated immune suppression. The massive infiltration of tumors by regulatory T cells (Tregs) prevents the development of a successful helper immune response. In this study, we investigated whether elimination of CD4(+) CD25(+) Tregs in the tumor microenvironment using anti-CD25 monoclonal antibodies (mAbs) was capable of enhancing CCL21-mediated antitumor immunity in a mouse hepatocellular carcinoma (HCC) model. We found that CCL21 in combination with anti-CD25 mAbs (PC61) resulted in improved antitumor efficacy and prolonged survival, not only inhibited tumor angiogenesis and cell proliferation, but also led to significant increases in the frequency of CD4(+), CD8(+) T cells and CD11c(+) DCs within the tumor, coincident with marked induction of tumor-specific CD8(+) cytotoxic T lymphocytes (CTLs) at the local tumor site. The intratumoral immune responses were accompanied by the enhanced elaboration of IL-12 and IFN-γ, but reduced release of the immunosuppressive mediators IL-10 and TGF-β1. The results indicated that depletion of Tregs in the tumor microenvironment could enhance CCL21-mediated antitumor immunity, and CCL21 combined with anti-CD25 mAbs may be a more effective immunotherapy to promote tumor rejection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology*
  • Antibodies, Monoclonal / therapeutic use
  • CD11c Antigen / metabolism
  • Carcinoma, Hepatocellular / blood supply
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemokine CCL21 / metabolism*
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Disease Progression
  • Female
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Regulation, Neoplastic / immunology
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-12 / biosynthesis
  • Interleukin-2 Receptor alpha Subunit / metabolism*
  • Liver Neoplasms / blood supply
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Inbred C57BL
  • Neovascularization, Pathologic
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Antibodies, Monoclonal
  • CD11c Antigen
  • Chemokine CCL21
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-12
  • Interferon-gamma

Grant support

This work was supported by National Natural Science Foundation of China (No. 31000527), Shanghai Health Bureau Research Fund for young investigator (to Dr. Shuang Zhou) and Hong Kong Scholar program (No. XJ2011025). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.