TY - JOUR
T1 - Adoptive transfer of tumor-reactive transforming growth factor-β-insensitive CD8+ T cells
T2 - Eradication of autologous mouse prostate cancer
AU - Zhang, Qiang
AU - Yang, Ximing
AU - Pins, Michael
AU - Javonovic, Borko
AU - Kuzel, Timothy
AU - Kim, Seong Jin
AU - Van Parijs, Luk
AU - Greenberg, Norman M.
AU - Liu, Victoria
AU - Guo, Yinglu
AU - Lee, Chung
PY - 2005/3/1
Y1 - 2005/3/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-04-3169
DO - 10.1158/0008-5472.CAN-04-3169
M3 - Article
C2 - 15753372
AN - SCOPUS:20144387943
SN - 0008-5472
VL - 65
SP - 1761
EP - 1769
JO - Cancer Research
JF - Cancer Research
IS - 5
ER -