The role of amino acid metabolism alterations in pancreatic cancer: From mechanism to application

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2023, Номер 1878(3), С. 188893 - 188893

Опубликована: Апрель 2, 2023

Язык: Английский

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

Cancer & Metabolism, Год журнала: 2023, Номер 11(1)

Опубликована: Май 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.

Язык: Английский

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L-Kynurenine participates in cancer immune evasion by downregulating hypoxic signaling in T lymphocytes

OncoImmunology, Год журнала: 2023, Номер 12(1)

Опубликована: Авг. 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.

Язык: Английский

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Supply and demand: Cellular nutrient uptake and exchange in cancer

Molecular Cell, Год журнала: 2021, Номер 81(18), С. 3731 - 3748

Опубликована: Сен. 1, 2021

Язык: Английский

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Pancreatic ductal adenocarcinoma cells reshape the immune microenvironment: Molecular mechanisms and therapeutic targets

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Год журнала: 2024, Номер 1879(6), С. 189183 - 189183

Опубликована: Сен. 19, 2024

Язык: Английский

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