The absence of invariant chain in MHC II cancer vaccines enhances the activation of tumor-reactive type 1 CD4+ T lymphocytes.
Activation of tumor-reactive T lymphocytes is a promising approach for the prevention and treatment of patients with metastatic cancers. Strategies that activate CD8(+) T cells are particularly promising because of the cytotoxicity and specificity of CD8(+) T cells for tumor cells. Optimal CD8(+) T cell activity requires the co-activation of CD4(+) T cells, which are critical for immune memory and protection against latent metastatic disease. Therefore, we are developing "MHC II" vaccines that activate tumor-reactive CD4(+) T cells. MHC II vaccines are MHC class I(+) tumor cells that are transduced with costimulatory molecules and MHC II alleles syngeneic to the prospective recipient. Because the vaccine cells do not express the MHC II-associated invariant chain (Ii), we hypothesized that they will present endogenously synthesized tumor peptides that are not presented by professional Ii(+) antigen presenting cells (APC) and will therefore overcome tolerance to activate CD4(+) T cells. We now report that MHC II vaccines prepared from human MCF10 mammary carcinoma cells are more efficient than Ii(+) APC for priming and boosting Type 1 CD4(+) T cells. MHC II vaccines consistently induce greater expansion of CD4(+) T cells which secrete more IFNgamma and they activate an overlapping, but distinct repertoire of CD4(+) T cells as measured by T cell receptor Vbeta usage, compared to Ii(+) APC. Therefore, the absence of Ii facilitates a robust CD4(+) T cell response that includes the presentation of peptides that are presented by traditional APC, as well as peptides that are uniquely presented by the Ii(-) vaccine cells.
Thompson
James A
JA
Department of Biological Sciences, University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore, MD 21250, USA.
Srivastava
Minu K
MK
Bosch
Jacobus J
JJ
Clements
Virginia K
VK
Ksander
Bruce R
BR
Ostrand-Rosenberg
Suzanne
S
D000938:Antigen-Presenting Cells / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D005434:Flow Cytometry / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D019496:Cancer Vaccines; D000949:Histocompatibility Antigens Class II; C045084:invariant chain