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Journal article
Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer
Cancer & metabolism, v 11(1), 7
24 May 2023
PMID: 37226257
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
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 their platinum-resistant counterpart (LLC-CR) cells. Humanized 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 170 mg/kg P.O. once a day for 15 days with and without anti-PD1 antibody (10 mg/kg, every 3 days). Immune profiles and KYN and tryptophan (TRP) production were evaluated.
Results
CR tumors exhibited a more highly immunosuppressive environment that debilitated robust anti-tumor immune responses. IDO1-mediated KYN production from CR cells suppressed NKG2D on immune effector natural killer (NK) and CD8(+) T cells and enhanced immunosuppressive populations of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Importantly, while selective IDO1 inhibition attenuated CR tumor growth, it concomitantly upregulated the TDO2 enzyme. To overcome the compensatory induction of TDO2 activity, we employed the 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. PD-L1 (programmed death-ligand-1) expression was increased in CR cells; therefore, we assessed dual inhibition + PD1 (programmed cell death protein-1) blocking and report profound anti-tumor growth and improved 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.
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Details
- Title
- Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer
- Creators
- Chunjing Wu - Miami VA Healthcare SystemSydney A. Spector - Miami VA Healthcare SystemGeorge Theodoropoulos - Miami VA Healthcare SystemDan J. M. Nguyen - Miami VA Healthcare SystemEmily Y. Kim - Miami VA Healthcare Syst, Dept Vet Affairs, Miami, FL 33125 USAAshley Garcia - Miami VA Healthcare SystemNiramol Savaraj - Miami VA Healthcare SystemDiane C. Lim - University of MiamiAnkita Paul - Drexel UniversityLynn G. Feun - University of MiamiMichael Bickerdike - Antido Therapeut Pty Ltd, Melbourne, AustraliaMedhi Wangpaichitr - University of Miami
- Publication Details
- Cancer & metabolism, v 11(1), 7
- Publisher
- Springer Nature
- Number of pages
- 22
- Grant note
- The author wants to thank Mr. Jose Gomez from the Miami VA hospital Pathology service for tissue processing and slide cutting. This work is supported by BLR&D Merit Review Award (1I01BX004371) and Career Development Award-2 (1K2BX001289) to MW; Sylvester Comprehensive Cancer Center (internal funding) to NS and LGF. NCI core support grant (1P30CA240139) to MW and DCL.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Electrical and Computer Engineering
- Web of Science ID
- WOS:000992892900001
- Other Identifier
- 991021861214904721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Cell Biology
- Oncology