Definition of key variables for the induction of optimal NY-ESO-1-specific T cells in HLA transgene mice.
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 ESO(123-137) peptide and subsequently with mature dendritic cells (DCs) presenting this and the A2-restriced ESO(157-165) epitope generated abundant, circulating, high-avidity primary and memory CD8(+) T cells that efficiently killed A2/ESO(157-165)(+) 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.
Johannsen
Alexandre
A
Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland.
Genolet
Raphaël
R
Legler
Daniel F
DF
Luther
Sanjiv A
SA
Luescher
Immanuel F
IF
D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000096:biosynthesis* / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology; D045142:Cross-Priming / Q000235:genetics / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D007117:Immunization, Secondary / Q000379:methods; D008565:Membrane Proteins / Q000008:administration & dosage / Q000096:biosynthesis* / Q000276:immunology*; D051379:Mice; D008805:Mice, Inbred A; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D006680:HLA Antigens; D008565:Membrane Proteins; D022223:Vaccines, Subunit