Central Role of IFNγ-Indoleamine 2,3-Dioxygenase Axis in Regulation of Interleukin-12-Mediated Antitumor Immunity

Sustained intratumoral delivery of interleukin-12 (IL-12) and granulocyte macrophage colony-stimulating factor induces tumor regression via restoration of tumor-resident CD8(+) T-effector/memory cell cytotoxicity and subsequent repriming of a secondary CD8(+) T-effector cell response in tumor-draining lymph nodes (TDLN). However, treatment-induced T-effector activity is transient and is accompanied with a CD4(+) CD25(+) Foxp3(+) T-suppressor cell rebound. Molecular and cellular changes in posttherapy tumor microenvironment and TDLN were monitored to elucidate the mechanism of counterregulation. Real-time PCR analysis revealed a 5-fold enhancement of indoleamine 2,3-dioxygenase (IDO) expression in the tumor and the TDLN after treatment. IDO induction required IFN gamma and persisted for up to 7 days. Administration of the IDO inhibitor D-1-methyl tryptophan concurrent with treatment resulted in a dramatic enhancement of tumor regression. Enhanced efficacy was associated with a diminished T-suppressor cell rebound, revealing a link between IDO activity and posttherapy regulation. Further analysis established that abrogation of the regulatory counterresponse resulted in a 10-fold increase in the intratumoral CD8(+) T-cell to CD4(+) Foxp3(+) T-cell ratio. The ratio of proliferating CD8(+) T-effector to CD4(+) Foxp3(+) T- suppressor cells was prognostic for efficacy of tumor suppression in individual mice. IFN gamma-dependent IDO induction and T- suppressor cell expansion were primarily driven by IL-12. These findings show a critical role for IDO in the regulation of IL-12-mediated antitumor immune responses. Cancer Res; 70(1); 129-38. (C)2010 AACR.