Adoptive immunotherapy with Cl-IB-MECA-treated CD8+ T cells reduces melanoma growth in mice

PLoS One. 2012;7(9):e45401. doi: 10.1371/journal.pone.0045401. Epub 2012 Sep 24.

Abstract

Cl-IB-MECA is a selective A3 adenosine receptor agonist, which plays a crucial role in limiting tumor progression. In mice, Cl-IB-MECA administration enhances the anti-tumor T cell-mediated response. However, little is known about the activity of Cl-IB-MECA on CD8+ T cells. The aim of this study was to investigate the effect of ex vivo Cl-IB-MECA treatment of CD8+ T cells, adoptively transferred in melanoma-bearing mice. Adoptive transfer of Cl-IB-MECA-treated CD8+ T cells or a single administration of Cl-IB-MECA (20 ng/mouse) inhibited tumor growth compared with the control group and significantly improved mouse survival. This was associated with the release of Th1-type cytokines and a greater influx of mature Langerin+ dendritic cells (LCs) into the tumor microenvironment. CD8+ T cells treated with Cl-IB-MECA released TNF-α which plays a critical role in the therapeutic efficacy of these cells when injected to mice. Indeed, neutralization of TNF-α by a specific monoclonal Ab significantly blocked the anti-tumor activity of Cl-IB-MECA-treated T cells. This was due to the reduction in levels of cytotoxic cytokines and the presence of fewer LCs. In conclusion, these studies reveal that ex vivo treatment with Cl-IB-MECA improves CD8+ T cell adoptive immunotherapy for melanoma in a TNF-α-dependent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / pharmacology
  • Adenosine A3 Receptor Agonists / pharmacology*
  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Immunohistochemistry
  • Immunotherapy, Adoptive / methods*
  • Melanoma / therapy*
  • Mice
  • Mice, Inbred C57BL

Substances

  • Adenosine A3 Receptor Agonists
  • Adenosine
  • 2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide

Grant support

This work was supported by grants from Provincia Avellino and FARB University of Salerno. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.