Adoptive transfer of tumor-reactive transforming growth factor-β-insensitive CD8+ T cells: Eradication of autologous mouse prostate cancer

Qiang Zhang, Ximing Yang, Michael Pins, Borko Javonovic, Timothy Kuzel, Seong Jin Kim, Luk Van Parijs, Norman M. Greenberg, Victoria Liu, Yinglu Guo, Chung Lee*

*Corresponding author for this work

Research output: Contribution to journalArticle

112 Scopus citations

Abstract

Transforming growth factor (TGF)-β is a potent immunosuppressant. Overproduction of TGF-β by tumor cells may lead to tumor evasion from the host immune surveillance and tumor progression. The present study was conducted to develop a treatment strategy through adoptive transfer of tumor-reactive TGF-β-insensitive CD8+ T cells. The mouse TRAMP-C2 prostate cancer cells produced large amounts of TGF-β1 and were used as an experimental model. C57BL/6 mice were primed with irradiated TRAMP-C2 cells. CD8+ T cells were isolated from the spleen of primed animals, were expanded ex vivo, and were rendered TGF-β insensitive by infecting with a retrovirus containing dominant-negative TGF-β type II receptor. Results of in vitro cytotoxic assay revealed that these CD8+ T cells showed a specific and robust tumor-killing activity against TRAMP-C2 cells but were ineffective against an irrelevant tumor line, B16-F10. To determine the in vivo antitumor activity, recipient mice were challenged with a single injection of TRAMP-C2 cells for a period up to 21 days before adoptive transfer of CD8 + T cells was done. Pulmonary metastasis was either eliminated or significantly reduced in the group receiving adoptive transfer of tumor-reactive TGF-β-insensitive CD8+ T cells. Results of immunofluorescent studies showed that only tumor-reactive TGF-β-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. Furthermore, transferred tumor-reactive TGF-β-insensitive CD8 + T cells were able to persist in tumor-bearing hosts but declined in tumor-free animals. These results suggest that adoptive transfer of tumor-reactive TGF-β-insensitive CD8+ T cells may warrant consideration for cancer therapy.

Original languageEnglish (US)
Pages (from-to)1761-1769
Number of pages9
JournalCancer Research
Volume65
Issue number5
DOIs
StatePublished - Mar 1 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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