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

Abstract

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-γ 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-1β) and CCL3 (MIP-1α) 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.