The MHC class II associated invariant chain limits the immunogenicity of genetically modified human tumor cell vaccines

Activation of tumor-reactive T lymphocytes is a promising approach for the treatment of patients with metastatic cancers. CD8 + T cells can have cytotoxicity and specificity for tumor cells and optimal CD8+ T cell activity and memory requires CD4 + T cell co-activation. Therefore, we are developing "MHC-II" vaccines that activate tumor-reactive CD4+ T cells. MHC-II vaccines are MHC class I+ tumor cells transduced with costimulatory molecules and MHC-II alleles syngeneic to the prospective recipient. In previous studies mouse MHC-II vaccines were therapeutic for established mouse tumors, provided they did not co-express the class II-associated Invariant chain (Ii), an accessory molecule coordinately regulated with MHC II. A major goal of my thesis has been to develop human MHC-II vaccines. I hypothesized that in the absence of Ii, MHC-II presents novel endogenously synthesized tumor peptides not presented by professional Ii+ antigen presenting cells (APC), thereby circumventing existing antigen-specific tumor-induced tolerance. To express a single MHC-II allele in the absence of Ii, MHC-II -Ii- cells were transduced with a bicistronic retroviral vector which expresses the MHC-II alpha and beta genes. To express multiple MHC-II alleles and to facilitate presentation of a broader repertoire of tumor antigens, tumor cells were transduced with the MHC-II transactivator (CIITA), a regulatory gene that coordinately increases expression of all MHC-II alleles. RNAi expression vectors silenced Ii >95% in CIITA/CD80/siRNA transductants. Down-regulation of Ii did not affect MHC-II expression or stability, and Ii + and Ii- transductants activate human CD4+ T cells to DRB1*0701-restricted HER2/neu epitopes. HER2/neu + MHC-II+ non-malignant cells (MCF10A) did not activate HER2/neu specific CD4+ T cells, suggesting tumor vaccines may not affect non-malignant tissues. MHC-II vaccines are more efficient than Ii+ APC for priming and boosting tumor-specific Type 1 CD4 + T cells, and they induce greater expansion of CD4+ T cells which secrete more IFNgamma and activate an overlapping, but distinct, repertoire of CD4+ T cells. Therefore, MHC-II vaccines facilitate a robust CD4+ T cell response that includes the presentation of peptides that are uniquely presented by Ii- cells. These vaccines may be unique agents which induce a strong tumor-specific immune response in patients.