The specificity and potency of the immune system make
immunotherapy a potential strategy for the treatment of
cancer. To exploit this potential, we have developed cell-based
cancer vaccines consisting of
tumor cells expressing syngeneic MHC class II and costimulatory molecules. The
vaccines mediate
tumor regression in mice and activate human CD4+ T cells in vitro. Previous
vaccines were generated by transducing MHC II negative
tumor cells with a single
HLA-DR allele. Because expression of multiple MHC II alleles would facilitate presentation of a broader repertoire of
tumor antigens, we have now transduced
tumor cells with the MHC
class II transactivator (CIITA), a regulatory gene that coordinately increases expression of all MHC II alleles. Previous studies in mice indicated that coexpression of the MHC II accessory molecule
invariant chain (Ii) inhibited presentation of endogenously synthesized
tumor antigens and reduced
vaccine efficacy. To determine if Ii expression affects presentation of MHC class II-restricted endogenously synthesized
tumor antigens in human
tumor cells, HLA-DR-MCF10
breast cancer cells were transduced with the CIITA, CD80 costimulatory molecule gene, and with or without small interfering RNAs (
siRNA) specific for Ii. Ii expression is silenced >95% in CIITA/CD80/
siRNA transductants; down-regulation of Ii does not affect
HLA-DR expression or stability; and Ii(+) and Ii(-) transductants activate human CD4+ T cells to DRB1*0701-restricted HER-2/neu
epitopes. Therefore,
tumor cells transduced with the CIITA, CD80, and with or without Ii
siRNA present endogenously synthesized
tumor antigens and are potential
vaccines for activating
tumor-specific CD4+ T cells.