BACKGROUND Monocarboxylate transporter 1 (MCT1) is a regulator of cell metabolism and a therapeutic target for cancer treatment. Understanding the changes in tumour function accompanying MCT1 inhibition will better characterise the anti-tumour effects of MCT1 inhibitors, potentially enabling the identification of pharmacodynamic biomarkers for the clinical development of these agents. METHODS We assessed the impact of the MCT1 inhibitor AZD3965 on tumour metabolism and immune cell infiltration as key determinants of tumour biological function in the MCT1-dependent Raji B cell lymphoma model. RESULTS Treatment of Raji xenograft-bearing severe combined immunodeficiency mice with AZD3965 led to inhibition of tumour growth paralleled with a decrease in tumour choline, as detected by non-invasive in vivo proton nuclear magnetic resonance spectroscopy. This effect was attributed to inhibition of phosphocholine de novo synthesis following decreased choline kinase α protein and messenger RNA expression that correlated with the AZD3965-induced build-up in intracellular lactate. These changes were concomitant with increased tumour immune cell infiltration involving dendritic and natural killer cells. CONCLUSIONS Our data provide new insights into the metabolic and cellular changes that occur in the tumour microenvironment following MCT1 blockade, which may contribute to the anti-tumour activity of AZD3965 and could have potential as pharmacodynamic biomarkers of MCT1 inhibition.

中文翻译：

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用AZD3965阻止单羧酸盐转运蛋白1抑制脂质的生物合成并增加肿瘤免疫细胞的浸润。

背景技术单羧酸盐转运蛋白1（MCT1）是细胞代谢的调节剂和癌症治疗的治疗靶标。了解伴随MCT1抑制作用的肿瘤功能变化将更好地表征MCT1抑制剂的抗肿瘤作用，从而有可能为这些药物的临床开发确定药效生物标志物。方法我们评估了MCT1抑制剂AZD3965对肿瘤代谢和免疫细胞浸润的影响，这是MCT1依赖性Raji B细胞淋巴瘤模型中肿瘤生物学功能的关键决定因素。结果用无创体内质子核磁共振波谱检测，用AZD3965治疗带有Raji异种移植的重度联合免疫缺陷小鼠可导致肿瘤生长受到抑制，同时肿瘤胆碱减少。该作用归因于胆碱激酶α蛋白和信使RNA表达的降低（与AZD3965-诱导的细胞内乳酸积累相关），从而抑制了磷酸胆碱从头合成。这些变化伴随着涉及树突状和自然杀伤细胞的肿瘤免疫细胞浸润的增加。结论我们的数据为MCT1阻断后肿瘤微环境中发生的代谢和细胞变化提供了新的见解，这可能有助于AZD3965的抗肿瘤活性，并可能具有抑制MCT1的药效生物标志物的潜力。