A new mechanism of tumor immune
resistance based on tryptophan degradation by indoleamine 2 ,3-dioxygenase
Ludwig
Institute for Cancer Research, Brussels Branch of Human Cell Genetics
Indoleamine 2,3-dioxygenase
(IDO) is an intracellular enzyme that catalyses rapid tryptophan degradation. Because tryptophan can freely cross the plasma membrane,
IDO expression results in a local depletion of tryptophan in the extracellular
medium surrounding the expressing cell. Tryptophan
depletion was shown to impair T lymphocyte proliferation, and therefore IDO
expression represents of powerful immunosuppressive mechanism that accounts,
for example, for maternal tolerance to allogeneic fetuses, where IDO expression
by placenta was found to play an essential role. Expression
of IDO can be induced by interferon-gamma in many cellular types, including
macrophages and dendritic cells, and appears to play a prominent role in immune
regulation.
To determine whether tumors
might use this mechanism to escape T-cell mediated immune rejection, we first
measured the expression of IDO in a series of murine and human tumor cell
lines. We found that many lines expressed the mRNA for IDO. We confirmed by Western blot that those lines also contained
the IDO protein, and by enzymatic assays that this protein was active. Moreover, when we tested a large series of human tumor
samples by immunohistochemistry using purified IDO-specific antibodies, we
observed that a vast majority stained positive, including all prostatic, colorectal,
pancreatic and cervical carcinomas. We conclude that
most human tumors express IDO.
To determine whether IDO expression provides
tumor cells with a survival advantage by allowing their escape from immune
rejection in vivo, we used the well-characterized model system of mouse tumor
P815, where the antigen encoded by gene P1A is the major target of the rejection
response. We observed that expression of IDO by P815
tumor cells prevents their rejection by pre-immunized mice. This effect can be partly reverted by systemic treatment
of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These
results suggest that the efficacy of therapeutic vaccination of cancer patients
could be improved by concomitant administration of an IDO inhibitor.