The molecular basis of MHC-mediated antigen presentation and cellular response in normal and cancer cells

Cytotoxic T lymphocytes recognize host cells that express new antigens as a result either of viral infection or transformation. Protein antigens are first degraded into fragments in cell cytoplasms, then transported to the endoplasmatic reticulum and eventually expressed on the cell surface, accomodated in a deep groove of class I molecules of the major histocompatibility complex. Even in absence of exogenous proteins, MHC molecules on the cell surface carry a large number of peptides derived from endogenous proteins. The isolation of such peptides, and the determination of their chemical structures, has permitted the identification of the characteristics ''anchor motifs'' for different MHC alloantigens. In these last years, there has been an increasing interest in the identification of peptides expressed preferentially or exclusively by cancer cells, since this information might help in finding a specific immunotherapy for malignant diseases. Several approaches have been used for this study, including the elution of peptides from MHC of tumor cells, followed by their purification, and by a test on their ability to render target cells susceptible to tumor-specific cytotoxic T lymphocytes; the synthesis of peptides known to be tumor-specific or tumor-dominant, followed by a test for their ability to activate a tumor-specific response has also been utilized. The complex mechanisms connected with cytotoxic T cells activation has been as well partly elucidated. All these data, although fragmentary and incomplete, allow a first insight into the complexity of the problems connected with cellular response to cancer, and partly explain the failure of cell defence against cancer progression.