Svena Verma, Sadna Budhu, Inna Serganova, Lauren Dong, Levi M Mangarin, Jonathan F Khan, Mamadou A Bah, Anais Assouvie, Yacine Marouf, Isabell Schulze, Roberta Zappasodi, Jedd D Wolchok, Taha Merghoub
{"title":"Pharmacologic LDH inhibition redirects intratumoral glucose uptake and improves antitumor immunity in solid tumor models.","authors":"Svena Verma, Sadna Budhu, Inna Serganova, Lauren Dong, Levi M Mangarin, Jonathan F Khan, Mamadou A Bah, Anais Assouvie, Yacine Marouf, Isabell Schulze, Roberta Zappasodi, Jedd D Wolchok, Taha Merghoub","doi":"10.1172/JCI177606","DOIUrl":null,"url":null,"abstract":"<p><p>Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":null,"pages":null},"PeriodicalIF":13.3000,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11364391/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Clinical Investigation","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1172/JCI177606","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
Tumor reliance on glycolysis is a hallmark of cancer. Immunotherapy is more effective in controlling glycolysis-low tumors lacking lactate dehydrogenase (LDH) due to reduced tumor lactate efflux and enhanced glucose availability within the tumor microenvironment (TME). LDH inhibitors (LDHi) reduce glucose uptake and tumor growth in preclinical models, but their impact on tumor-infiltrating T cells is not fully elucidated. Tumor cells have higher basal LDH expression and glycolysis levels compared with infiltrating T cells, creating a therapeutic opportunity for tumor-specific targeting of glycolysis. We demonstrate that LDHi treatment (a) decreases tumor cell glucose uptake, expression of the glucose transporter GLUT1, and tumor cell proliferation while (b) increasing glucose uptake, GLUT1 expression, and proliferation of tumor-infiltrating T cells. Accordingly, increasing glucose availability in the microenvironment via LDH inhibition leads to improved tumor-killing T cell function and impaired Treg immunosuppressive activity in vitro. Moreover, combining LDH inhibition with immune checkpoint blockade therapy effectively controls murine melanoma and colon cancer progression by promoting effector T cell infiltration and activation while destabilizing Tregs. Our results establish LDH inhibition as an effective strategy for rebalancing glucose availability for T cells within the TME, which can enhance T cell function and antitumor immunity.
肿瘤依赖糖酵解是癌症的一大特征。由于肿瘤乳酸外流减少和肿瘤微环境(TME)中葡萄糖供应增加,免疫疗法在控制缺乏乳酸脱氢酶(LDH)的低糖酵解肿瘤方面更为有效。在临床前模型中,LDH 抑制剂(LDHi)可减少葡萄糖摄取和肿瘤生长,但其对肿瘤浸润 T 细胞的影响尚未完全阐明。与浸润T细胞相比,肿瘤细胞具有更高的基础LDH表达和糖酵解水平,这为肿瘤特异性靶向糖酵解创造了治疗机会。我们证明,LDHi 处理(a)会降低肿瘤细胞的葡萄糖摄取、葡萄糖转运体 GLUT1 的表达和肿瘤细胞的增殖,而(b)会增加肿瘤浸润 T 细胞的葡萄糖摄取、GLUT1 的表达和增殖。因此,通过抑制 LDH 增加微环境中的葡萄糖供应量可改善体外杀伤肿瘤 T 细胞的功能,并削弱 Treg 的免疫抑制活性。此外,将 LDH 抑制与免疫检查点阻断疗法相结合,可在促进效应 T 细胞浸润和活化的同时破坏 Treg 的稳定性,从而有效控制小鼠黑色素瘤和结肠癌的进展。我们的研究结果表明,LDH 抑制是重新平衡 TME 内 T 细胞葡萄糖供应的有效策略,可增强 T 细胞功能和抗肿瘤免疫力。
期刊介绍:
The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science.
The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others.
The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.