Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy

Nature Medicine. 11, 312 - 319 (2005)

Speaker：王瑋祥                             Time：2005/06/15, 14:10~15:00

Commentator：蕭璦莉 老師                   Place：Room 601

Abstract：

   Immune escape is a hallmark of cancer progression, but its underlying molecular genetic basis remains poorly understood. Previous studies of BAR (Bin/Amphiphysin/Rvs) adapter encoding gene Bin1 (also known as Amphiphysin2) indicate that it functions in cancer suppression, endocytosis, actin organization, apoptosis, transcription and vesicle trafficking. In this paper, the authors showed that Bin1 is involved in controlling expression of the Indo gene, which encodes the indoleamine 2,3-dioxygenase (IDO), an immunoregulatory enzyme overexpressed in many cancers. IDO catalyzes the initial rate-limiting step in tryptophan catabolism that leads tryptophan depletion in local microenvironments and therefore blocks activation of T lymphocytes, which are particularly sensitive to loss of this essential amino acid. The authors used Bin-/- deletion, cMyc-HRas1 transgenic murine embryo keratinocytes (MR-KEC -/-) to prove that Bin1 loss promotes tumor formation by immune escape, including T-cell and APC, but does not change tumor cell phenotype or in vitro cell proliferation. They also indicated that Bin1 deletion potentiates the NF-B- and STAT-dependent expression of Indo in siRNA or dominant inhibitory experiments. Furthermore, they used 1MT, an IDO inhibitor, to define that IDO activity is very important to Bin1 loss caused immune escape for tumor formation. Finally, they found out that cancer chemotherapy combined with 1MT will markedly cause more tumor regression than used cytotoxic agents or 1MT alone, without increasing the effective dose of cytotoxic agents. This evidence also can be seen in using a new IDO inhibitor, MTH-trp, combined with paclitaxel. These findings are the first study to link IDO to a cancer suppression pathway, and that proposes IDO as an attractive and tractable target for the development of small-molecule immunomodulatory drugs to safely leverage the efficacy of standard chemotherapeutic agents.

References：

1.      Muller AJ, et al. Targeted disruption of the murine Bin1/Amphiphysin II gene does not disable endocytosis but results in embryonic cardiomyopathy with aberrant myofibril formation. Mol Cell Biol. 23(12), 4295-306,2003.

2.      Uyttenhove C, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase.Nat Med. 9(10),1269-74,2003.