| Author |
Gurusamy, Devikala Singh, Vinod Bronte, Vincenzo Zhu, Ziqiang Hurwitz, Arthur A. Leighty, Robert Cuss, Steven M. Shoe, Jennifer L. |
| Description |
Author Affiliation: Zhu Z ( 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); Cuss SM ( 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); Singh V ( 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); Gurusamy D ( 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); Shoe JL ( Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick, MD 21072); Leighty R ( Data Management Services, National Cancer Institute, Frederick MD, 21702); Bronte V ( Department of Pathology and Diagnostics, Immunology Section, University of Verona, 37134 Verona, Italy.); Hurwitz AA ( 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) |
| 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. |
| Subject Keyword |
Antibody Affinity Immunology Cd4-positive T-lymphocytes Cd8-positive T-lymphocytes Cytotoxicity, Immunologic Immune Tolerance Animals Genetics Antigens, Neoplasm Cell Line, Tumor Dendritic Cells Epitopes, T-lymphocyte Lymphocyte Activation Melanoma Mice Mice, Inbred C57bl Mice, Transgenic Research Support, N.i.h., Intramural Discipline Immunology |
