Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy, and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit.
SUMMARY To fulfill bioenergetic demands of activation, T cells perform aerobic glycolysis, a process common to highly proliferative cells in which glucose is fermented into lactate rather than oxidized in mitochondria. However, the signaling events that initiate aerobic glycolysis in T cells remain unclear. We show T cell activation rapidly induces glycolysis independent of transcription, translation, CD28, and Akt and not involving increased glucose uptake or activity of glycolytic enzymes. Rather, TCR signaling promotes activation of pyruvate dehydrogenase kinase 1 (PDHK1), inhibiting mitochondrial import of pyruvate and facilitating breakdown into lactate. Inhibition of PDHK1 reveals this switch is required acutely for cytokine synthesis but dispensable for cytotoxicity. Functionally, cytokine synthesis is modulated via lactate dehydrogenase, which represses cytokine mRNA translation when aerobic glycolysis is disengaged. Our data provide mechanistic insight to metabolic contribution to effector T cell function and suggest that T cell function may be finely tuned through modulation of glycolytic activity.
Introduction To assess the safety and efficacy of ultrasound (US)-guided percutaneous nephrolithotomy (PCNL) for complex renal stones when performed in a modified supine position.Methods We retrospectively reviewed the charts of patients who underwent PCNL for complex renal stones at our institution between August 2018 and December 2021. During this time, 188 consecutive patients underwent US-guided PCNL in the prone position (P group, n=129) or in the flank-free modified supine position (S group, n=59). Patient demographics and intraoperative and postoperative data were analyzed.Results Successful renal access was achieved in all patients. The baseline demographics were comparable between the two groups. The numbers of renal access was significantly higher (2.1±0.4 vs 1.2±0.2, p=0.002) and the operation time was comparable (79.1±14.6 minutes vs 96.2±19.6 minutes, p=0.06) between the two groups. The postoperative hospital stay was also shorter in the P group (6.2±1.5 d vs 10.2±1.7 d, p=0.008). The postoperative hemoglobin loss was similar between the P and S groups (1.7±0.4 g/dl vs 1.8±0.3 g/dl, p=0.12). The stone-free rate (SFR) was significantly lower in the S group (57.5% vs 82.7%, p<0.001). There were no embolization or septic complications. Twelve patients (20.3%) in the S group underwent simultaneous or staged retrograde flexible ureteroscopy to remove residual stones.Conclusion US-guided PCNL in the modified supine position was a safe treatment for complex renal stones. However, the single-session stone clearance rate was not ideal. The supine flank-free position may be unsuitable for US-guided PCNL in patients with complex renal stones.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.