Indoleamine 2,3-Dioxygenase, An Emerging Target for Anti- Cancer Therapy
Pp. 296-327 (32)
Xiangdong Liu, Robert C. Newton, Steven M. Friedman and Peggy A. Scherle
The inability of the host immune system to control tumor growth appears to
result from dominant mechanisms of immune suppression that prevent the immune
system from effectively responding in a way that consistently results in tumor rejection.
Among the many possible mediators of tumoral immune escape, the immunoregulatory
enzyme, indoleamine 2,3-dioxygenase (IDO), has recently gained considerable
attention. IDO is a heme-containing, monomeric oxidoreductase that catalyzes the first
and rate-limiting step in the degradation of the essential amino acid tryptophan to
N-formyl-kynurenine. Tryptophan depletion as well as the accumulation of its
metabolites results in a strongly inhibitory effect on the development of immune
responses by blocking T cell activation, inducing T cell apoptosis and promoting the
differentiation of naïve T cells into cells with a regulatory phenotype (Tregs). Recent data
obtained from preclinical tumor models demonstrate that IDO inhibition can
significantly enhance the antitumor activity of various chemotherapeutic and
immunotherapeutic agents. These results, coupled with data showing that increased IDO
expression is an independent prognostic variable for reduced overall survival in cancer
patients, suggest that IDO inhibition may represent an effective strategy to treat
malignancies, either alone or in combination with chemotherapeutics or other immune
based therapies. This review will focus on the role of IDO as a mediator of peripheral
immune tolerance, evidence that IDO becomes dysregulated in human cancers, and the
latest progress on the development of IDO inhibitors as a novel anti-cancer therapy.
Cancer and anti-cancer, dendritic cells, immune suppression or
tolerance, indoleamine 2, 3-dioxygenase, L-tryptophan, kynurenine, T cells.
Incyte Corporation, Wilmington, DE 19880, USA.