Enhancing the recognition of tumour associated antigens.

Activated CD8+ T cells (TCD8+) can directly recognize malignant cells because processed fragments of tumour associated antigens (TAA), 8-10 amino acids in length and complexed with MHC class I molecules, are displayed on tumour cell surfaces. Tumour cells have been genetically modified in a variety of ways in efforts to enhance the immune recognition of TAA. An alternative strategy is the expression of TAA in recombinant or synthetic form. This has been made possible by the recent cloning of TAA recognized by TCD8+. In this communication we review recent work in our own laboratory on the expression of TAA as synthetic peptide, by "naked" plasmid DNA injected intramuscularly or transdermally, and by recombinant viruses including vaccinia (rVV), fowlpox (rFV) and adenovirus (rAd). The expression of TAA in recombinant and synthetic forms allows increased control over the quantity, location, and kinetics of TAA presentation and can result in powerful, specific, anti-tumour immune responses.

Molecular mechanisms used by tumors to escape immune recognition: immunogenetherapy and the cell biology of major histocompatibility complex class I.

In this article, we explore the hypothesis that tumor cells can escape recognition by CD8+ T cells via deficiencies in antigen processing and presentation. Aspects of the molecular and cellular biology of major histocompatibility complex class I are reviewed. Evidence for histology-specific molecular mechanisms in the antigen-processing and -presentation deficiencies observed in some human and murine tumors is presented. Mechanisms identified include down-regulation of antigen processing, loss of functional beta 2-microglobulin, and deletion of specific alpha-chain alleles. Finally, we discuss studies using an antigen-presentation-deficient mouse tumor as a model for the immunogenetherapy of an antigen-presentation deficiency.