title: Adoptive transfer of tumor-reactive transforming growth factor-beta-insensitive CD8+ T cells: eradication of autologous mouse prostate cancer.
abstract: Transforming growth factor (TGF)-beta is a potent immunosuppressant. Overproduction of TGF-beta 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-beta-insensitive CD8+ T cells. The mouse TRAMP-C2 prostate cancer cells produced large amounts of TGF-beta1 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-beta insensitive by infecting with a retrovirus containing dominant-negative TGF-beta 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-beta-insensitive CD8+ T cells. Results of immunofluorescent studies showed that only tumor-reactive TGF-beta-insensitive CD8+ T cells were able to infiltrate into the tumor and mediate apoptosis in tumor cells. Furthermore, transferred tumor-reactive TGF-beta-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-beta-insensitive CD8+ T cells may warrant consideration for cancer therapy.
authors.affiliation: Department of Urology, Northwestern University's Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ximing
authors.initials: X
authors.lastname: Yang
authors.forename: Michael
authors.initials: M
authors.lastname: Pins
authors.forename: Borko
authors.initials: B
authors.lastname: Javonovic
authors.forename: Timothy
authors.initials: T
authors.lastname: Kuzel
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Luk Van
authors.initials: LV
authors.lastname: Parijs
authors.forename: Norman M
authors.initials: NM
authors.lastname: Greenberg
authors.forename: Victoria
authors.initials: V
authors.lastname: Liu
authors.forename: Yinglu
authors.initials: Y
authors.lastname: Guo
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D005799:Genes, Dominant; D049452:Green Fluorescent Proteins; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D012878:Skin Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000276:immunology / Q000378:metabolism*
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II