T-cell tolerance to tumor-associated
self-antigens: implications for tumor therapy?
Tumor
Immunology Program, Division of Cellular Immunology, German Cancer Research
Center, INF 280, D-69120 Heidelberg, Germany.
The prevailing notion that tolerance
to peripheral self-antigens is solely covered by post-thymic mechanisms has
been questioned by the recent finding that tissue-specific antigens are expressed
by thymic stromal cells, a phenomenon termed promiscuous gene expression.
Thymic medullary epithelial cells (mTEC) of mice and man express a unique
range of tissue antigens at the mRNA level when compared to other antigen
presenting cells or epithelial cells of other tissues. This set of genes (>
400) includes many tissue-specific antigens, which apparently do not share
structural or functional commonalities. Notably, this gene pool encompasses
clinically relevant
auto-antigens and cancer-germ line genes. Self-antigen expression, when
restricted to mTEC, is sufficient to confer specific T-cell tolerance attesting
to its functional role. The unequivocal and specific expression of tumor-associated
antigens in human mTEC, in particular those of the cancer-germ line group,
calls for a reappraisal of their immune-privileged status. Cancer-germ line
antigens had so far only been found in male germ cells, a few cells of the
uterus and tumor cells. Since male germ cells lack MHC expression and the
testis is sequestered from circulating lymphocytes, it had been assumed that
these antigens are precluded from tolerance. Given the exquisite sensitivity
of central tolerance, even the low and variable expression of these tumor
antigens, may result in some degree of self-tolerance. Whether thymic tolerance
induction contributes to the limited success of current clinical vaccination
trials with peptides derived from these antigens remains so far conjectural.