Galloway Jason E, Holderbaum Andrea M, Arya Namrata, Zhang Suohui, Bodnar Michael S, Norman Ruthann, Carson William E, Yu Lianbo, Kendra Kari L, Burd Christin E
Department of Molecular Genetics, The Ohio State University College of Arts and Sciences, Columbus, OH 43210.
Department of Cancer Biology and Genetics, The Ohio State University College of Medicine, Columbus, OH 43210.
Aging Cancer. 2020 Dec;1(1-4):58-70. doi: 10.1002/aac2.12012. Epub 2020 Sep 17.
The impact of biologic aging on immune checkpoint inhibitor (ICI) toxicity and efficacy is underexplored in metastatic melanoma (MM). In peripheral blood T-lymphocytes (PBTLs), biologic aging is characterized by changes in T-cell composition and cellular senescence. Whether indicators of PBTL biologic aging vary in MM patients or can be used to predict premature ICI discontinuation (pID) is unknown.
We prospectively collected PBTLs from 117 cancer-free controls and 46 MM patients scheduled to begin pembrolizumab or nivolumab monotherapy. 74 mRNAs indicative of T-cell subsets, activation, co-stimuation/inhibition and cellular senescence were measured by Nanostring. Relationships between each mRNA and chronologic age were assessed in patients and controls. Candidate biomarkers were identified by calculating the hazard ratio (HR) for pID in patients divided into low and high groups based on log-transformed mRNA levels or the magnitude by which each mRNA measurement deviated from the control trend (Δage). Area under the curve (AUC) analyses explored the ability of each biomarker to discriminate between patients with and without pID at 6 months and 1 year.
Fifteen mRNAs correlated with chronologic age in controls, including markers of T-cell subsets, differentiation, cytokine production and co-stimulation/inhibition. None of these mRNAs remained correlated with age in patients. Median follow-up was 94.8 (1.6-195.7) weeks and 35 of 46 patients discontinued therapy (23 progression, 7 toxicity, 5 comorbidity/patient preference). Elevated pre-therapy (HR 2.2[1.1-4.9]), (HR 2.9[1.4-5.8]) and (HR 2.2[1.1-4.5]) levels predicted pID independent of Δage-correction. and predicted pID only after Δage-correction (HR 2.5[1.3-5.1]; 3.7[1.8-7.8]; 2.1[1.1-4.3]). AUC analysis identified Δage- and as candidate predictors of pID (AUC=0.73; 0.75).
Correlations between transcriptional markers of PBTL composition and chronologic age are disrupted in MM. Correcting for normal, age-related trends in biomarker expression unveils new biomarker candidates predictive of ICI outcomes.
在转移性黑色素瘤（MM）中，生物衰老对免疫检查点抑制剂（ICI）毒性和疗效的影响尚未得到充分研究。在外周血T淋巴细胞（PBTL）中，生物衰老的特征是T细胞组成的变化和细胞衰老。MM患者中PBTL生物衰老的指标是否存在差异，或者是否可用于预测ICI提前停药（pID）尚不清楚。
我们前瞻性地收集了117名无癌对照者和46名计划开始帕博利珠单抗或纳武利尤单抗单药治疗的MM患者的PBTL。通过纳米串技术检测了74种指示T细胞亚群、激活、共刺激/抑制和细胞衰老的mRNA。评估了患者和对照中每种mRNA与实际年龄之间的关系。通过计算根据对数转换后的mRNA水平或每种mRNA测量值偏离对照趋势的幅度（Δ年龄）分为低分组和高分组的患者中pID的风险比（HR），确定候选生物标志物。曲线下面积（AUC）分析探讨了每种生物标志物在6个月和1年时区分有pID和无pID患者的能力。
15种mRNA与对照中的实际年龄相关，包括T细胞亚群、分化、细胞因子产生和共刺激/抑制的标志物。在患者中，这些mRNA均不再与年龄相关。中位随访时间为94.8（1.6-195.7）周，46名患者中有35名停止治疗（23例进展、7例毒性反应、5例合并症/患者偏好）。治疗前升高的 （HR 2.2[1.1-4.9]）、 （HR 2.9[1.4-5.8]）和 （HR 2.2[1.1-4.5]）水平可独立于Δ年龄校正预测pID。 和 仅在Δ年龄校正后预测pID（HR 2.5[1.3-5.1]；3.7[1.8-7.8]；2.1[1.1-4.3]）。AUC分析确定Δ年龄和 为pID的候选预测指标（AUC=0.73；0.75）。
MM中PBTL组成的转录标志物与实际年龄之间的相关性被破坏。校正生物标志物表达中正常的、与年龄相关的趋势可揭示预测ICI结局的新候选生物标志物。
