Loss of TSTAs andor their presentation

A simple explanation for the ability of an originally antigenic neoplasm to grow in an immune animal is that it has lost its TSTAs as a result of selection by the immune system. Since tumor rejection is most commonly mediated by CD8+ T cells with CTL activity, loss of major histocompatibility complex (MHC) class I molecules, and/or molecules involved in antigen processing and transport will produce the same result, i.e. lack of epitopes for CTLs to recognize.

There is, indeed, evidence that neoplastic cells can lose TSTAs and/or MHC class I antigens. However, the frequency of total loss of such antigens may be lower than that suggested by immunohistology. Furthermore, both TSTAs and MHC class 1 molecules are commonly expressed by tumor cells growing in immune animals, implying that a failed presentation of TSTA does not provide a general explanation as to why tumor immunity is not more effective. However, it is clearly one of the mechanisms that can lead to the selection of tumors that are not sensitive to immune destruction by CD8+ T cells.

Some tumor antigens, such as the TSTAs of poly-omavirus-induced neoplasms, cannot be lost without loss of the neoplastic phenotype, since the molecule detected as a tumor antigen is involved in the neoplastic transformation. On the other hand, some tumor-associated differentiation antigens can be eliminated without loss of malignancy. It is noteworthy that polyomavirus-induced mouse tumors did retain their sensitivity to an immune response directed to the polyoma TSTA even after attempts to select for TSTA-negative cells by prolonged tumor passage in immune animals, since this indicates that their ability to present the polyoma TSTAs via MHC class I molecules remained intact.

Substantially higher cell surface expression of MHC class I molecules is needed for a rumor cell to induce an immune response than to serve as its target, and there is evidence that tumor cells may still be killed by CD8" lymphocytes even when their MHC class I expression is too low to be detectable by immunohistology. Furthermore, the expression of MHC class I molecules can be upregulated, e.g. following exposure to interferon y. This suggests that immune T cells may be effective in a larger number of cases than might be indicated by the frequent downregulation of MHC during tumor progression. One should also bear in mind that tumor cells which have lost MHC class I molecules are likely to become more sensitive to destruction by natural killer (NK) cells.

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