Ex vivo culture with interleukin (IL)-12 improves CD8(+) T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFN-gamma but requires perforin.
Cancer Res
; 66(9): 4913-21, 2006 May 01.
Article
em En
| MEDLINE
| ID: mdl-16651448
ABSTRACT
In animal models and clinical trials, adoptive transfer of activated, antigen-specific CD8(+) T cells mediates tumor regression in a cell dose-dependent manner. The cytokine interleukin (IL)-12 promotes CD8(+) T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-gamma release. We have shown that culturing CD8(+) T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Activated ovalbumin-specific CD8(+) T cells cultured with IL-12, IL-18, both, or neither were assayed for antigen-specific cytokine production and cytolytic activity and adoptively transferred to C57BL/6 mice with established tumors. Maximal IFN-gamma release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure. T cells cultured with IL-12 more effectively eliminated tumors, and addition of IL-18 did not further augment responses. IFN-gamma-deficient CD8(+) T cells showed effective antitumor activity that was enhanced by IL-12 with or without IL-18. Perforin-deficient CD8(+) T cells were poor mediators of antitumor activity, though, and showed no improvement after culture with IL-12 and/or IL-18. Thus, ex vivo culture with IL-12 was sufficient to augment antigen-specific in vitro cytotoxicity and antitumor activity in vivo in an IFN-gamma-independent but perforin-dependent manner. Ex vivo culture with IL-12 may improve CD8(+) T-cell immunotherapy of cancer in the absence of donor cell-derived IFN-gamma via perforin-mediated cytolysis.
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Base de dados:
MEDLINE
Assunto principal:
Glicoproteínas de Membrana
/
Leucemia Mieloide
/
Imunoterapia Adotiva
/
Interleucina-12
/
Linfócitos T CD8-Positivos
/
Interleucina-18
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Cancer Res
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
Estados Unidos