Scarpa Joseph R, Montagna Giacomo, Plitas George, Gulati Amitabh, Fischer Gregory W, Mincer Joshua S
Department of Anesthesiology, Weill Cornell Medicine, New York, NY, United States.
Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, United States.
Front Oncol. 2023 Sep 14;13:1267532. doi: 10.3389/fonc.2023.1267532. eCollection 2023.
Opioids are the primary analgesics for cancer pain. Recent clinical evidence suggests opioids may counteract the effect of immune checkpoint inhibition (ICI) immunotherapy, but the mechanism for this interaction is unknown. The following experiments study how opioids and immunotherapy modulate a common RNA expression pathway in triple negative breast cancer (TNBC), a cancer subtype in which immunotherapy is increasingly used. This study identifies a mechanism by which opioids may decrease ICI efficacy, and compares ketamine, a non-opioid analgesic with emerging use in cancer pain, for potential ICI interaction.
Tumor RNA expression and clinicopathologic data from a large cohort with TNBC (N=286) was used to identify RNA expression signatures of disease. Various drug-induced RNA expression profiles were extracted from multimodal RNA expression datasets and analyzed to estimate the RNA expression effects of ICI, opioids, and ketamine on TNBC.
We identified a RNA expression network in CD8 T-cells that was relevant to TNBC pathogenesis and prognosis. Both opioids and anti-PD-L1 ICI regulated RNA expression in this network, suggesting a nexus for opioid-ICI interaction. Morphine and anti-PD-L1 therapy regulated RNA expression in opposing directions. By contrast, there was little overlap between the effect of ketamine and anti-PD-L1 therapy on RNA expression.
Opioids and ICI may target a common immune network in TNBC and regulate gene expression in opposing fashion. No available evidence supports a similar interaction between ketamine and ICI.
阿片类药物是癌症疼痛的主要镇痛药。最近的临床证据表明，阿片类药物可能会抵消免疫检查点抑制（ICI）免疫疗法的效果，但这种相互作用的机制尚不清楚。以下实验研究了阿片类药物和免疫疗法如何调节三阴性乳腺癌（TNBC）中一种常见的RNA表达途径，TNBC是一种越来越多地使用免疫疗法的癌症亚型。本研究确定了阿片类药物可能降低ICI疗效的机制，并比较了氯胺酮（一种在癌症疼痛中新兴应用的非阿片类镇痛药）与ICI的潜在相互作用。
使用来自一大群TNBC患者（N = 286）的肿瘤RNA表达和临床病理数据来识别疾病的RNA表达特征。从多模态RNA表达数据集中提取各种药物诱导的RNA表达谱，并进行分析以评估ICI、阿片类药物和氯胺酮对TNBC的RNA表达影响。
我们在CD8 T细胞中确定了一个与TNBC发病机制和预后相关的RNA表达网络。阿片类药物和抗PD-L1 ICI均调节该网络中的RNA表达，提示阿片类药物与ICI相互作用的联系。吗啡和抗PD-L1疗法以相反方向调节RNA表达。相比之下，氯胺酮和抗PD-L1疗法对RNA表达的影响几乎没有重叠。
阿片类药物和ICI可能靶向TNBC中一个共同的免疫网络，并以相反的方式调节基因表达。没有现有证据支持氯胺酮与ICI之间存在类似的相互作用。
