Ex vivo culture with interleukin (IL)-12 improves CD8+ T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFN-γ but requires perforin

Jennifer N. MacGregor, Qiao Li, Alfred E. Chang, Thomas M. Braun, Dennis P.M. Hughes, Kevin T. McDonagh

Research output: Contribution to journalArticle

26 Citations (Scopus)

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-γ 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, DL-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-γ release occurred after T-cell culture with IL-12 and DL-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-γ-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-γ-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-γ via perforin-mediated cytolysis.

Original languageEnglish (US)
Pages (from-to)4913-4921
Number of pages9
JournalCancer research
Volume66
Issue number9
DOIs
StatePublished - May 1 2006

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Adoptive Immunotherapy
Perforin
Interleukin-18
Interleukin-12
Leukemia
T-Lymphocytes
Ovalbumin
Neoplasms
Cytokines
Antigens
CD8 Antigens
Adoptive Transfer
Myeloid Cells
Inbred C57BL Mouse
Acute Myeloid Leukemia
Immunotherapy
Up-Regulation
Animal Models
Cell Culture Techniques
Clinical Trials

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Ex vivo culture with interleukin (IL)-12 improves CD8+ T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFN-γ but requires perforin. / MacGregor, Jennifer N.; Li, Qiao; Chang, Alfred E.; Braun, Thomas M.; Hughes, Dennis P.M.; McDonagh, Kevin T.

In: Cancer research, Vol. 66, No. 9, 01.05.2006, p. 4913-4921.

Research output: Contribution to journalArticle

MacGregor, Jennifer N. ; Li, Qiao ; Chang, Alfred E. ; Braun, Thomas M. ; Hughes, Dennis P.M. ; McDonagh, Kevin T. / Ex vivo culture with interleukin (IL)-12 improves CD8+ T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFN-γ but requires perforin. In: Cancer research. 2006 ; Vol. 66, No. 9. pp. 4913-4921.
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AU - McDonagh, Kevin T.

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AB - 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-γ 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, DL-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-γ release occurred after T-cell culture with IL-12 and DL-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-γ-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-γ-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-γ via perforin-mediated cytolysis.

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