Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer
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 i...
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| Format: | Article |
| Language: | English |
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BMC
2023-05-01
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| Series: | Cancer & Metabolism |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40170-023-00307-1 |
| _version_ | 1797817857201930240 |
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| author | Chunjing Wu Sydney A. Spector George Theodoropoulos Dan J. M. Nguyen Emily Y. Kim Ashley Garcia Niramol Savaraj Diane C. Lim Ankita Paul Lynn G. Feun Michael Bickerdike Medhi Wangpaichitr |
| author_facet | Chunjing Wu Sydney A. Spector George Theodoropoulos Dan J. M. Nguyen Emily Y. Kim Ashley Garcia Niramol Savaraj Diane C. Lim Ankita Paul Lynn G. Feun Michael Bickerdike Medhi Wangpaichitr |
| author_sort | Chunjing Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T08:59:38Z |
| format | Article |
| id | doaj.art-a0383d87afed462586cb405c53f2010f |
| institution | Directory Open Access Journal |
| issn | 2049-3002 |
| language | English |
| last_indexed | 2024-03-13T08:59:38Z |
| publishDate | 2023-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cancer & Metabolism |
| spelling | doaj.art-a0383d87afed462586cb405c53f2010f2023-05-28T11:25:39ZengBMCCancer & Metabolism2049-30022023-05-0111112210.1186/s40170-023-00307-1Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancerChunjing Wu0Sydney A. Spector1George Theodoropoulos2Dan J. M. Nguyen3Emily Y. Kim4Ashley Garcia5Niramol Savaraj6Diane C. Lim7Ankita Paul8Lynn G. Feun9Michael Bickerdike10Medhi Wangpaichitr11Department of Veterans Affairs, Miami VA Healthcare SystemDepartment of Veterans Affairs, Miami VA Healthcare SystemDepartment of Veterans Affairs, Miami VA Healthcare SystemDepartment of Veterans Affairs, Miami VA Healthcare SystemDepartment of Veterans Affairs, Miami VA Healthcare SystemDepartment of Veterans Affairs, Miami VA Healthcare SystemDepartment of Veterans Affairs, Miami VA Healthcare SystemDepartment of Veterans Affairs, Miami VA Healthcare SystemDepartment of Electrical and Computer Engineering, Drexel UniversityDepartment of Medicine, University of Miami School of MedicineAntido Therapeutics Pty LtdDepartment of Veterans Affairs, Miami VA Healthcare SystemAbstract 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.https://doi.org/10.1186/s40170-023-00307-1Lung cancerKynurenineDual IDO1/TDO2 inhibitorsCisplatin resistanceImmunometabolismDrug resistance |
| spellingShingle | Chunjing Wu Sydney A. Spector George Theodoropoulos Dan J. M. Nguyen Emily Y. Kim Ashley Garcia Niramol Savaraj Diane C. Lim Ankita Paul Lynn G. Feun Michael Bickerdike Medhi Wangpaichitr Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer Cancer & Metabolism Lung cancer Kynurenine Dual IDO1/TDO2 inhibitors Cisplatin resistance Immunometabolism Drug resistance |
| title | Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer |
| title_full | Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer |
| title_fullStr | Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer |
| title_full_unstemmed | Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer |
| title_short | Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer |
| title_sort | dual inhibition of ido1 tdo2 enhances anti tumor immunity in platinum resistant non small cell lung cancer |
| topic | Lung cancer Kynurenine Dual IDO1/TDO2 inhibitors Cisplatin resistance Immunometabolism Drug resistance |
| url | https://doi.org/10.1186/s40170-023-00307-1 |
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