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Fig. 1 | Cancer & Metabolism

Fig. 1

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

Fig. 1

Increased KYN suppressed NKG2D expression of NK and CD8 + T cells. A Human PBMCs (hPBMCs) were cultured in the presence of an activator (CD2/28 + IL2) for 48 h. On day 3, cells were washed and the proliferation rate of lymphocytes was determined by assessing the reduction of the intensity of the fluorescent cell-permeable dye CFSE. B Growth inhibitory effect: PBMCs were exposed to activators, washed, and assayed for cell viability at each time point. C Results of NK + and CD8 + T cell expansion at each time point before and after the removing activator. D After activators were removed, activated hPBMCs were exposed to KYN at the indicated concentrations for another 48 h. We observed cytotoxic effects above 100 μM. E Using the same experimental conditions as 1D, the percent of NKG2D on NK + and CD8 + T cells were evaluated after KYN treatment. F Immunoblot of NKG2D from activated hPBMCs treated with increasing concentrations of KYN for 48 h. G Pro-inflammatory cytokine TNFα was quantified by the LEGENDplex™ bead-based immunoassay. H Immunometabolism scheme in cisplatin-resistant (CR) NSCLC cells. (1) CR lung cancer cells uptake less glucose and are no longer addicted to glycolysis compared to sensitive cells. (2) CR cells utilize amino acids (i.e., glutamine) as their main carbon skeleton source to survive. (3) Increased oxidative metabolism (OXMET) leads to increased accumulation of intracellular ROS. (4) ROS activates the KYN pathway via a ROS-dependent enzyme (IDO1) resulting in significant TRP uptake and greater KYN production. (5) Increased extracellular KYN activates Treg and suppresses NKG2D. CR cells with high IDO1 activity recruit and activate MDSCs via Treg [15]. PDL1 expression by CR cells and MDSCs further inhibits immune effector populations. In all the experiments, data are presented as mean ± SEM of 3 independent experiments and were analyzed using one-way ANOVA followed by Dunnett’s multiple comparisons with *P < 0.05, **P < 0.005, ***P < 0.0005)

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