CTLA-4 blockade induces indoleamine 2,3-dioxygenase where treatment with 1- methyl-d-tryptophan displays greater treatment effect in tumors with high ido expression

Abstract

Background: As hepatocellular carcinoma (HCC) traditionally occurs in chronically inflamed livers, these tumors are often immunogenic and therefore potential targets for immunotherapy. CTLA-4 blockade has been utilized in two trails in HCC with promising results. However, not all patients have the same response to therapy by a largely unknown mechanism. Indoleamine 2,3- dioxygenase (IDO) with its two forms, IDO1 and IDO2, is part of kynurenine pathway for the metabolism of the essential amino acid tryptophan. It has been demonstrated that IDO acts as an immunosuppressive enzyme altering the tumor microenvironment and is upregulated in inflammatory states with the most potent inducer being IFN-γ. High levels of IDO in tumors including HCC have been associated with a poor prognosis. This study aimed at identifying IDO as a potential mechanism of immune escape from CTLA-4 directed therapy. Methods: The drug 1-methyl-D-tryptophan (1-D-MT), which has been shown to inhibit IDO2 activity, was utilized alone or in combination with a CTLA-4 blocking antibody in treatment of mice with subcutaneous and orthotropic HCC. Induction of IDO RNA in tumor cells was evaluated by quantitative polymerase chain reaction (qPCR). Results: Combination therapy with 1-D-MT and an anti-CTLA-4 blocking antibody produces a greater anti-tumor effect in both a subcutaneous and orthotropic model than either drug alone. Additionally, tumors with high IDO induction showed a better response to combination treatment. Mice injected with anti-CTLA-4 antibody showed higher IDO2 expression in tumors. Conclusion: These results provide evidence that IDO expression induces an additional effect of immunosuppression in the tumor microenvironment, especially after anti-CTLA-4 therapy, and support a combination therapy with IDO inhibitors for a successful immunotherapy treatment.