MHC class I down-regulation: tumour escape from immune surveillance? (review).

Malignant conversion and subsequent in vivo selection can give rise to the cell populations that show stable expression of an immune escape phenotype, MHC class I deficient neoplasms. Deficiencies associated with the MHC class I down-regulation are either irreversible, such as beta2 microglobulin and class I heavy chain gene disabling mutations, or reversible. The reversible MHC class I deficiencies involve all levels of the MHC class I-restricted antigen presentation machinery. They can be repaired, at least partially and in vitro, by cytokines (IFNgamma, TNFalpha) or by DNA demethylation/histone hyperacetylation procedures. The reduced levels of MHC class I antigens result in decreased sensitivity to MHC class I-restricted, cytotoxic T lymphocyte-mediated lysis, the major component of the tumour rejection reaction. MHC class I down-regulation helps tumour cells evade the classical T cell-dependent immune responses but simultaneously imposes another, the NK cell-mediated, surveillance stimulated by the 'missing self' signals. The innate and adaptive antitumour immunity may be under some conditions interconnected: primary activation of the MHC class I-unrestricted surveillance mechanisms may lead to the production of IFNgamma by the activated NK/gammadelta T cells; the in situ produced IFNgamma may then up-regulate the MHC class I molecule expression on the tumour cell surface and in this way it may stimulate the more efficient, MHC class I-restricted, adaptive immunity. If we accept that the MHC class I down-regulation can, under some conditions, indeed be a mechanism of the tumour escape from the immune defence, the problem arises how to cope efficiently with this escape. Either therapeutic procedures aiming at up-regulation of MHC class I expression, or enhancement of MHC class I-unrestricted (CD4+, NK, NKT, gammadelta T) tumour defence effector mechanisms by dendritic cell-based therapeutic vaccines, by cytokines (IL-2, IL-12, IFNgamma, GM-CSF), or by the cytokine gene-based, genetically modified tumour vaccines should be considered.