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Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses.

Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ - J. Exp. Med. (2001)

Bottom Line: Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2(180-188)-specific CTLs detected in the periphery.The synergism in the effects of CTLA-4 blockade and depletion of CD25(+) Treg cells indicates that CD25(+) Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity.Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunohematology and Blood Transfusion, Tumor Immunology Lab, E3-Q, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.

ABSTRACT
Therapeutic efficacy of a tumor cell-based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte-associated antigen (CTLA)-4 pathway or the CD25(+) regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25(+) Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2(180-188)-specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8(+) T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25(+) Treg cells indicates that CD25(+) Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.

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IFN-γ release in response to TRP-2180–188 peptide. Splenocytes from mice were in vitro restimulated with irradiated B16/B7.1 and tested for recognition of TRP-2180–188 peptide-loaded target cells in an IFN-γ release assay 1 wk later. Treatments of mice are described in legend to Fig. 5. Values indicate average from three measurements with SD indicated. One representative experiment of two is shown.
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Figure 6: IFN-γ release in response to TRP-2180–188 peptide. Splenocytes from mice were in vitro restimulated with irradiated B16/B7.1 and tested for recognition of TRP-2180–188 peptide-loaded target cells in an IFN-γ release assay 1 wk later. Treatments of mice are described in legend to Fig. 5. Values indicate average from three measurements with SD indicated. One representative experiment of two is shown.

Mentions: To analyze the functional activity of the TRP-2–specific CTLs detected by tetramer staining, we measured, directly ex vivo, intracellular IFN-γ production in CD8+ T cells derived from vaccine draining lymph nodes in response to TRP-2 peptide. Fig. 5 B shows that TRP-2–specific IFN-γ production can be detected in CD8+ T cells from mice that received the B16-GM-CSF vaccine in combination with CD25 depletion and CTLA-4 blockade. In the absence of CD25 depletion or CTLA-4 blockade the numbers of IFN-γ–producing CTLs are decreased, similarly as found for tetramer staining. As expected, the percentage of specific CTLs was higher in the vaccine draining lymph nodes than in the blood. We also analyzed IFN-γ release by splenocyte cultures in the presence of the TRP-2180–188 peptide (Fig. 6). The IFN-γ release data showed that TRP-2180–188–specific CTL immunity can be detected in splenocyte cultures from mice that had received treatment with GM-CSF–producing vaccine and CTLA-4 blockade and that this activity is markedly increased in mice that had also undergone CD25 depletion (Fig. 6, no. 4).


Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses.

Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, Toes RE, Offringa R, Melief CJ - J. Exp. Med. (2001)

IFN-γ release in response to TRP-2180–188 peptide. Splenocytes from mice were in vitro restimulated with irradiated B16/B7.1 and tested for recognition of TRP-2180–188 peptide-loaded target cells in an IFN-γ release assay 1 wk later. Treatments of mice are described in legend to Fig. 5. Values indicate average from three measurements with SD indicated. One representative experiment of two is shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195955&req=5

Figure 6: IFN-γ release in response to TRP-2180–188 peptide. Splenocytes from mice were in vitro restimulated with irradiated B16/B7.1 and tested for recognition of TRP-2180–188 peptide-loaded target cells in an IFN-γ release assay 1 wk later. Treatments of mice are described in legend to Fig. 5. Values indicate average from three measurements with SD indicated. One representative experiment of two is shown.
Mentions: To analyze the functional activity of the TRP-2–specific CTLs detected by tetramer staining, we measured, directly ex vivo, intracellular IFN-γ production in CD8+ T cells derived from vaccine draining lymph nodes in response to TRP-2 peptide. Fig. 5 B shows that TRP-2–specific IFN-γ production can be detected in CD8+ T cells from mice that received the B16-GM-CSF vaccine in combination with CD25 depletion and CTLA-4 blockade. In the absence of CD25 depletion or CTLA-4 blockade the numbers of IFN-γ–producing CTLs are decreased, similarly as found for tetramer staining. As expected, the percentage of specific CTLs was higher in the vaccine draining lymph nodes than in the blood. We also analyzed IFN-γ release by splenocyte cultures in the presence of the TRP-2180–188 peptide (Fig. 6). The IFN-γ release data showed that TRP-2180–188–specific CTL immunity can be detected in splenocyte cultures from mice that had received treatment with GM-CSF–producing vaccine and CTLA-4 blockade and that this activity is markedly increased in mice that had also undergone CD25 depletion (Fig. 6, no. 4).

Bottom Line: Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2(180-188)-specific CTLs detected in the periphery.The synergism in the effects of CTLA-4 blockade and depletion of CD25(+) Treg cells indicates that CD25(+) Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity.Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunohematology and Blood Transfusion, Tumor Immunology Lab, E3-Q, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.

ABSTRACT
Therapeutic efficacy of a tumor cell-based vaccine against experimental B16 melanoma requires the disruption of either of two immunoregulatory mechanisms that control autoreactive T cell responses: the cytotoxic T lymphocyte-associated antigen (CTLA)-4 pathway or the CD25(+) regulatory T (Treg) cells. Combination of CTLA-4 blockade and depletion of CD25(+) Treg cells results in maximal tumor rejection. Efficacy of the antitumor therapy correlates with the extent of autoimmune skin depigmentation as well as with the frequency of tyrosinase-related protein 2(180-188)-specific CTLs detected in the periphery. Furthermore, tumor rejection is dependent on the CD8(+) T cell subset. Our data demonstrate that the CTL response against melanoma antigens is an important component of the therapeutic antitumor response and that the reactivity of these CTLs can be augmented through interference with immunoregulatory mechanisms. The synergism in the effects of CTLA-4 blockade and depletion of CD25(+) Treg cells indicates that CD25(+) Treg cells and CTLA-4 signaling represent two alternative pathways for suppression of autoreactive T cell immunity. Simultaneous intervention with both regulatory mechanisms is therefore a promising concept for the induction of therapeutic antitumor immunity.

Show MeSH
Related in: MedlinePlus