Definition of Key Variables for the Induction of Optimal NY-ESO-1-Specific T Cells in HLA Transgene Mice

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2010
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Johannsen, Alexandre
Genolet, Raphael
Luther, Sanjiv A.
Luescher, Immanuel F.
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An attractive treatment of cancer consists in inducing tumor-eradicating CD8+ CTL specific for tumor-associated Ags, such as NY-ESO-1 (ESO), a strongly immunogenic cancer germ line gene-encoded tumor-associated Ag, widely expressed on diverse tumors. To establish optimal priming of ESO-specific CTL and to define critical vaccine variables and mechanisms, we used HLA-A2/DR1 H-2-/- transgenic mice and sequential immunization with immunodominant DR1- and A2-restricted ESO peptides. Immunization of mice first with the DR1-restricted ESO123-137 peptide and subsequently with mature dendritic cells (DCs) presenting this and the A2-restriced ESO157-165 epitope generated abundant, circulating, high-avidity primary and memory CD8+ T cells that efficiently killed A2/ESO157-165+ tumor cells. This prime boost regimen was superior to other vaccine regimes and required strong Th1 cell responses, copresentation of MHC class I and MHC class II peptides by the same DC, and resulted in upregulation of sphingosine 1-phosphate receptor 1, and thus egress of freshly primed CD8+ T cells from the draining lymph nodes into circulation. This well-defined system allowed detailed mechanistic analysis, which revealed that 1) the Th1 cytokines IFN-gamma and IL-2 played key roles in CTL priming, namely by upregulating on naive CD8+ T cells the chemokine receptor CCR5; 2) the inflammatory chemokines CCL4 (MIP-1beta) and CCL3 (MIP-1alpha) chemoattracted primed CD4+ T cells to mature DCs and activated, naive CD8+ T cells to DC-CD4 conjugates, respectively; and 3) blockade of these chemokines or their common receptor CCR5 ablated priming of CD8(+) T cells and upregulation of sphingosine 1-phosphate receptor 1. These findings provide new opportunities for improving T cell cancer vaccines.

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570 Biowissenschaften, Biologie
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ISO 690JOHANNSEN, Alexandre, Raphael GENOLET, Daniel F. LEGLER, Sanjiv A. LUTHER, Immanuel F. LUESCHER, 2010. Definition of Key Variables for the Induction of Optimal NY-ESO-1-Specific T Cells in HLA Transgene Mice. In: The Journal of Immunology. 2010, 185(6), pp. 3445-3455. ISSN 0022-1767. eISSN 1550-6606. Available under: doi: 10.4049/jimmunol.1001397
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@article{Johannsen2010-09-15Defin-36057,
  year={2010},
  doi={10.4049/jimmunol.1001397},
  title={Definition of Key Variables for the Induction of Optimal NY-ESO-1-Specific T Cells in HLA Transgene Mice},
  number={6},
  volume={185},
  issn={0022-1767},
  journal={The Journal of Immunology},
  pages={3445--3455},
  author={Johannsen, Alexandre and Genolet, Raphael and Legler, Daniel F. and Luther, Sanjiv A. and Luescher, Immanuel F.}
}
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    <dcterms:abstract xml:lang="eng">An attractive treatment of cancer consists in inducing tumor-eradicating CD8&lt;sup&gt;+&lt;/sup&gt; CTL specific for tumor-associated Ags, such as NY-ESO-1 (ESO), a strongly immunogenic cancer germ line gene-encoded tumor-associated Ag, widely expressed on diverse tumors. To establish optimal priming of ESO-specific CTL and to define critical vaccine variables and mechanisms, we used HLA-A2/DR1 H-2&lt;sup&gt;-/-&lt;/sup&gt; transgenic mice and sequential immunization with immunodominant DR1- and A2-restricted ESO peptides. Immunization of mice first with the DR1-restricted ESO&lt;sub&gt;123-137&lt;/sub&gt; peptide and subsequently with mature dendritic cells (DCs) presenting this and the A2-restriced ESO&lt;sub&gt;157-165&lt;/sub&gt; epitope generated abundant, circulating, high-avidity primary and memory CD8&lt;sup&gt;+&lt;/sup&gt; T cells that efficiently killed A2/ESO&lt;sub&gt;157-165&lt;/sub&gt;&lt;sup&gt;+&lt;/sup&gt; tumor cells. This prime boost regimen was superior to other vaccine regimes and required strong Th1 cell responses, copresentation of MHC class I and MHC class II peptides by the same DC, and resulted in upregulation of sphingosine 1-phosphate receptor 1, and thus egress of freshly primed CD8&lt;sup&gt;+&lt;/sup&gt; T cells from the draining lymph nodes into circulation. This well-defined system allowed detailed mechanistic analysis, which revealed that 1) the Th1 cytokines IFN-gamma and IL-2 played key roles in CTL priming, namely by upregulating on naive CD8&lt;sup&gt;+&lt;/sup&gt; T cells the chemokine receptor CCR5; 2) the inflammatory chemokines CCL4 (MIP-1beta) and CCL3 (MIP-1alpha) chemoattracted primed CD4&lt;sup&gt;+&lt;/sup&gt; T cells to mature DCs and activated, naive CD8&lt;sup&gt;+&lt;/sup&gt; T cells to DC-CD4 conjugates, respectively; and 3) blockade of these chemokines or their common receptor CCR5 ablated priming of CD8(+) T cells and upregulation of sphingosine 1-phosphate receptor 1. These findings provide new opportunities for improving T cell cancer vaccines.</dcterms:abstract>
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