T 细胞耐受分数可预测免疫相关不良事件。
T-cell tolerant fraction as a predictor of immune-related adverse events.
机构信息
Peter O'Donnell School of Public Health, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
出版信息
J Immunother Cancer. 2023 Aug;11(8). doi: 10.1136/jitc-2022-006437.
BACKGROUND
Immune checkpoint inhibitor (ICI) therapies may cause unpredictable and potentially severe autoimmune toxicities termed immune-related adverse events (irAEs). Because T cells mediate ICI effects, T cell profiling may provide insight into the risk of irAEs. Here we evaluate a novel metric-the T-cell tolerant fraction-as a predictor of future irAEs.
METHODS
We examined T-cell receptor beta (TRB) locus sequencing from baseline pretreatment samples from an institutional registry and previously published studies. For each patient, we used TRB sequences to calculate the T-cell tolerant fraction, which was then assessed as a predictor of future irAEs (classified as Common Terminology Criteria for Adverse Event grade 0-1 vs grade ≥2). We then compared the tolerant fraction to TRB clonality and diversity. Finally, the tolerant fraction was assessed on (1) T cells enriched against napsin A, a potential autoantigen of irAEs; (2) thymic versus peripheral blood T cells; and (3) TRBs specific for various infections and autoimmune diseases.
RESULTS
A total of 77 patients with cancer (22 from an institutional registry and 55 from published studies) receiving ICI therapy (43 CTLA4, 19 PD1/PDL1, 15 combination CTLA4+PD1/PDL1) were included in the study. The tolerant fraction was significantly lower in cases with clinically significant irAEs (p<0.001) and had an area under the receiver operating curve (AUC) of 0.79. The tolerant fraction was lower for each ICI treatment category, reaching statistical significance for CTLA4 (p<0.001) and demonstrating non-significant trends for PD1/PDL1 (p=0.21) and combination ICI (p=0.18). The tolerant fraction for T cells enriched against napsin A was lower than other samples. The tolerant fraction was also lower in thymic versus peripheral blood samples, and lower in some (multiple sclerosis) but not other (type 1 diabetes) autoimmune diseases. In our study cohort, TRB clonality had an AUC of 0.62, and TRB diversity had an AUC of 0.60 for predicting irAEs.
CONCLUSIONS
Among patients receiving ICI, the baseline T-cell tolerant fraction may serve as a predictor of clinically significant irAEs.
背景
免疫检查点抑制剂（ICI）疗法可能会引起称为免疫相关不良反应（irAEs）的不可预测且潜在严重的自身免疫毒性。由于 T 细胞介导了 ICI 的作用，因此 T 细胞分析可能有助于了解 irAEs 的风险。在这里，我们评估了一种新的指标——T 细胞耐受分数，作为预测 irAEs 的指标。
方法
我们检查了来自机构注册处和以前发表的研究的基线预处理样本中的 T 细胞受体β（TRB）基因座测序。对于每个患者，我们使用 TRB 序列计算 T 细胞耐受分数，然后将其评估为未来 irAEs 的预测指标（分为 CTCAE 不良事件通用术语标准 0-1 级与≥2 级）。然后，我们将耐受分数与 TRB 克隆性和多样性进行比较。最后，我们在以下方面评估了耐受分数：（1）针对 napin A（irAEs 的潜在自身抗原）进行富集的 T 细胞；（2）胸腺与外周血 T 细胞；（3）针对各种感染和自身免疫性疾病的 TRB。
结果
共纳入 77 名接受 ICI 治疗的癌症患者（22 名来自机构注册处，55 名来自已发表的研究）（43 名 CTLA4，19 名 PD1/PDL1，15 名 CTLA4+PD1/PDL1）。有临床意义的 irAEs 的病例耐受分数明显较低（p<0.001），其受试者工作特征曲线（AUC）下面积为 0.79。每个 ICI 治疗类别中的耐受分数均较低，达到 CTLA4 的统计学意义（p<0.001），并且 PD1/PDL1（p=0.21）和联合 ICI（p=0.18）呈非显著趋势。针对 napin A 进行富集的 T 细胞的耐受分数低于其他样本。与外周血样本相比，胸腺样本的耐受分数也较低，而在某些（多发性硬化症）但不是其他（1 型糖尿病）自身免疫性疾病中则较低。在我们的研究队列中，TRB 克隆性的 AUC 为 0.62，TRB 多样性的 AUC 为 0.60，用于预测 irAEs。
结论
在接受 ICI 治疗的患者中，基线 T 细胞耐受分数可作为预测临床上有意义的 irAEs 的指标。
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