免疫检查点抑制剂（ICI）疗法可能引发不可预测且潜在严重的自身免疫毒性反应，被称为免疫相关不良事件（irAEs）。由于T细胞介导ICI的作用，T细胞谱系分析可能有助于了解irAEs的风险。在本研究中，我们评估了一种新的指标——T细胞耐受分数，作为未来irAEs的预测指标。我们检查了来自机构登记和先前发表研究的基线治疗前样本中的T细胞受体β（TRB）基因定序。对于每个患者，我们利用TRB序列计算T细胞耐受分数，并将其作为预测未来irAEs（按不良事件的临床术语规定分为0-1级和≥2级）的指标进行评估。然后，我们将耐受分数与TRB克隆性和多样性进行了比较。最后，我们在以下方面评估了耐受分数：（1）富集了napsin A的T细胞，napsin A是irAEs的潜在自身抗原；（2）胸腺与外周血T细胞；（3）特定于各种感染和自身免疫性疾病的TRB。 共有77例接受ICI治疗（43例CTLA4，19例PD1/PDL1，15例CTLA4+PD1/PDL1组合）的癌症患者被纳入研究（22例来自机构登记，55例来自发表的研究）。临床上有意义的irAEs病例中的耐受分数明显较低（p<0.001），并具有0.79的接收者操作特征曲线下面积（AUC）。每个ICI治疗类别的耐受分数都较低，对于CTLA4组存在统计学意义（p<0.001），而对于PD1/PDL1组（p=0.21）和ICI组合（p=0.18）则显示非显著性趋势。针对napsin A富集的T细胞的耐受分数低于其他样本。胸腺样本中的耐受分数也较低，并且部分自身免疫疾病（多发性硬化症）低于其他自身免疫疾病（1型糖尿病）。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。 在接受ICI治疗的患者中，基线的T细胞耐受分数可能作为临床上有意义的irAEs的预测指标。© 作者（或其雇主）2023。根据CC BY-NC授权进行再使用。不得进行商业再使用。详见权限和权限。由BMJ出版。

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.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.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.Among patients receiving ICI, the baseline T-cell tolerant fraction may serve as a predictor of clinically significant irAEs.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.