Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer

Background: The impact of non-small cell lung cancer (NSCLC) metabolism on the immune microenvironment is not well understood within platinum resistance. We have identified crucial metabolic differences between cisplatin-resistant (CR) and cisplatin-sensitive (CS) NSCLC cells with elevated indoleamine 2,3-dioxygenase-1 (IDO1) activity in CR, recognized by increased kynurenine (KYN) production. Methods Co-Culture, syngeneic, and humanize mice models were utilized. C57BL/6 mice were inoculated with either Lewis lung carcinoma mouse cells (LLC) or its platinum-resistant counterpart (LLC-CR) cells. Humanize mice were inoculated with either A (human CS cells) or ALC (human CR cells). Mice were treated with either IDO1 inhibitor or TDO2 (tryptophan 2,3-dioxygenase-2) inhibitor at 200 mg/kg P.O. once a day for 15 days; or with a new-in-class IDO1/TDO2 dual inhibitor AT-0174 at 170mg/kg P.O. once a day for 15 days with and without anti-PD1 antibody (10 mg/kg, every 3 days). Immune profiles as well as KYN and tryptophan (TRP) productions were evaluated. Results CR tumors exhibited a more highly immunosuppressive environment and blocked the anti-tumor immune response. IDO1-mediated KYN production from CR cells suppressed NKG2D on immune effector natural killer (NK) and CD8 + T cells and enhanced immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Importantly, while the selective IDO1 inhibitor attenuated CR tumor growth, it concomitantly upregulated the TDO2 enzyme. To overcome the compensatory induction of TDO2 activity, we employed IDO1/TDO2 dual inhibitor, AT-0174. Dual inhibition of IDO1/TDO2 in CR mice suppressed tumor growth to a greater degree than IDO1 inhibition alone. Significant enhancement in NKG2D frequency on NK and CD8 + T cells and a reduction in Tregs and MDSCs were observed following AT-1074 treatment. Additionally, CR cells possessed an increased expression of PD-L1 (programmed death-ligand-1); therefore, we assessed the dual inhibition + PD1 (programmed cell death protein-1) blocking and report a profound anti-tumor growth and immunity in CR tumors which in turn extended overall survival in mice. Conclusion Our study reports the presence of platinum-resistant lung tumors that utilize both IDO1/TDO2 enzymes for survival and to escape immune surveillance as a consequence of KYN metabolites. We also report early in vivo data in support of the potential therapeutic efficacy of the dual IDO1/TDO2 inhibitor AT-0174 as a part of immuno-therapeutic treatment that disrupts tumor metabolism and enhances anti-tumor immunity.