Molecular Cell, Journal Year: 2021, Volume and Issue: 81(18), P. 3731 - 3748
Published: Sept. 1, 2021
Language: Английский
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2023, Volume and Issue: 1878(3), P. 188893 - 188893
Published: April 2, 2023
Language: Английский
Citations
15
Cancer & Metabolism, Journal Year: 2023, Volume and Issue: 11(1)
Published: May 24, 2023
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, humanize mice models were utilized. C57BL/6 inoculated either Lewis carcinoma mouse (LLC) or their platinum-resistant counterpart (LLC-CR) cells. Humanized A (human CS cells) ALC CR cells). Mice treated IDO1 inhibitor TDO2 (tryptophan 2,3-dioxygenase-2) at 200 mg/kg P.O. once a day for 15 days; new-in-class, IDO1/TDO2 dual AT-0174 170 days without anti-PD1 antibody (10 mg/kg, every 3 days). Immune profiles KYN tryptophan (TRP) production evaluated. Results tumors exhibited more highly immunosuppressive environment that debilitated robust anti-tumor responses. IDO1-mediated from suppressed NKG2D effector natural killer (NK) CD8 + T enhanced populations regulatory (Tregs) myeloid-derived suppressor (MDSCs). Importantly, while selective inhibition attenuated tumor growth, it concomitantly upregulated enzyme. To overcome compensatory induction activity, we employed inhibitor, AT-0174. Dual growth to greater degree than alone. Significant enhancement frequency NK reduction Tregs MDSCs observed following AT-1074 treatment. PD-L1 (programmed death-ligand-1) expression was cells; therefore, assessed PD1 death protein-1) blocking report profound improved immunity which turn extended overall survival mice. Conclusion Our study reports presence utilize both enzymes survival, escape surveillance as consequence metabolites. also early vivo data support potential therapeutic efficacy part immuno-therapeutic treatment disrupts enhances immunity.
Language: Английский
Citations
15
OncoImmunology, Journal Year: 2023, Volume and Issue: 12(1)
Published: Aug. 10, 2023
Malignant tumors often escape anticancer immune surveillance by suppressing the cytotoxic functions of T lymphocytes. While many these evasion networks include checkpoint proteins, small molecular weight compounds, such as amino acid L-kynurenine (LKU), could also substantially contribute to suppression anti-cancer immunity. However, biochemical mechanisms underlying suppressive effects LKU on T-cells remain unclear. Here, we report for first time that suppresses cell function an aryl hydrocarbon receptor (AhR) ligand. The presence in cells is associated with AhR activation, which results competition between and hypoxia-inducible factor 1 alpha (HIF-1α) nuclear translocator, ARNT, leading exhaustion. expression indoleamine 2,3-dioxygenase (IDO1, enzyme leads generation) induced TGF-β-Smad-3 pathway. We show IDO-negative cancers utilize alternative route production via endogenous inflammatory mediator, high mobility group box (HMGB-1)-interferon-gamma (IFN-γ) axis. In addition, other (like T-cell lymphomas) trigger IDO1 activation eosinophils present tumor microenvironment (TME). These suppress function, thus support machinery.
Language: Английский
Citations
14
Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2024, Volume and Issue: 1879(6), P. 189183 - 189183
Published: Sept. 19, 2024
Language: Английский
Citations
5
Molecular Cell, Journal Year: 2021, Volume and Issue: 81(18), P. 3731 - 3748
Published: Sept. 1, 2021
Language: Английский
Citations
30