title: CD4+ T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8+ T Cells.
abstract: Maintaining antitumor immunity remains a persistent impediment to cancer immunotherapy. We and others have previously reported that high-avidity CD8(+) T cells are more susceptible to tolerance induction in the tumor microenvironment. In the present study, we used a novel model where T cells derived from two independent TCR transgenic mouse lines recognize the same melanoma antigenic epitope but differ in their avidity. We tested whether providing CD4(+) T cell help would improve T cell responsiveness as a function of effector T cell avidity. Interestingly, delivery of CD4(+) T cell help during in vitro priming of CD8(+) T cells improved cytokine secretion and lytic capacity of high-avidity T cells, but not low-avidity T cells. Consistent with this observation, copriming with CD4(+) T cells improved antitumor immunity mediated by higher avidity, melanoma-specific CD8(+) T cells, but not T cells with similar specificity but lower avidity. Enhanced tumor immunity was associated with improved CD8(+) T cell expansion and reduced tolerization, and it was dependent on presentation of both CD4(+) and CD8(+) T cell epitopes by the same dendritic cell population. Our findings demonstrate that CD4(+) T cell help preferentially augments high-avidity CD8(+) T cells and provide important insight for understanding the requirements to elicit and maintain durable tumor immunity.
authors: Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702;
authors: Ziqiang
authors: Z
authors: Zhu
authors: Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702;
authors: Steven M
authors: SM
authors: Cuss
authors: Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702;
authors: Vinod
authors: V
authors: Singh
authors: Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702;
authors: Devikala
authors: D
authors: Gurusamy
authors: Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick, MD 21072;
authors: Jennifer L
authors: JL
authors: Shoe
authors: Data Management Services, National Cancer Institute, Frederick MD, 21702; and.
authors: Robert
authors: R
authors: Leighty
authors: Department of Pathology and Diagnostics, Immunology Section, University of Verona, 37134 Verona, Italy.
authors: Vincenzo
authors: V
authors: Bronte
authors: Tumor Immunity and Tolerance Section, Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD 21702; Andy.Hurwitz@Agenusbio.com.
authors: Arthur A
authors: AA
authors: Hurwitz
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000235:genetics / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte