Inhibition of indoleamine 2,3-dioxygenase enhances graft-versus-leukemia effect after donor leukocyte infusion in mice: differential efficacy of 1-methyl tryptophan isomers (TRAN3P.907)

Abstract

Abstract Indoleamine 2,3-dioxygenase (IDO) is the first and rate-limiting enzyme of tryptophan catabolism through kynurenine (KYN) pathway, has an important role in immunomodulation. Moreover, it was shown that treating mice with 1-methyl tryptophan (1-MT), a small-molecule inhibitor of IDO, could break the tolerogenic state, providing antitumor responses. Despite the role of IDO in the induction of tumor immune tolerance, the direct role of IDO inhibition on GVL and GVHD still remains obscure. We established a murine GVL model. Recipient mice were sublethally irradiated and were transplanted with donor bone marrow cells on day 0. Recipient mice were receiving with or without DLI on day 14. Two isomers of IDO inhibition (D-1MT and L-1MT, 100mg/kg) were administered for 5 days per week from the day of P815 cell inoculation until 4 weeks. Both 1-MT isomers administration reduced leukemia growth in mice with CC. On the other hand, L-1MT but not D-1MT reduced leukemia growth in mice with MC. IDO expressions was increased in TDLN and tumor tissues of the CC mice but not in the MC mice. Accordingly plasma concentrations of KYN were increased in the CC mice on day 14 and treatment of both 1-MT isomers abrogated its production. These results demonstrate both isomers of 1-MT enhanced DLI-induced GVL after transplantation, possibly mediated by inhibition of IDO activity in the tumor microenvironment. L-1MT but not D-1MT may directly abrogate leukemia growth regardless of the expressions of IDO.