NEW YORK – By systematically profiling T-cell receptor (TCR) patterns and tumor-infiltrating lymphocyte (TIL) antigen recognition repertoires in the tumor microenvironment of pediatric brain cancers, a University of Pittsburgh-led team has identified T-cell features with apparent ties to survival that may eventually serve as prognostic markers or treatment clues in children with often-deadly brain tumors..

纽约——通过系统地分析儿童脑癌肿瘤微环境中的T细胞受体（TCR）模式和肿瘤浸润淋巴细胞（TIL）抗原识别库，匹兹堡大学领导的团队发现了与生存率明显相关的T细胞特征，这些特征最终可能成为预后标志物或治疗线索，用于患有高致命性脑瘤的儿童。

The findings

研究结果

appeared

出现

in

在

Science Translational Medicine

科学转化医学

on Wednesday

在周三

.

。

'This study is part of our laboratory's overall research focused on the urgent need of identifying new feasible, safe, and effective immunotherapies for kids with brain tumors,'

“这项研究是我们实验室总体研究的一部分，重点是迫切需要为患有脑瘤的儿童找到新的可行、安全且有效的免疫疗法。”

senior author Gary Kohanbash, a neurological surgery researcher affiliated with the UPMC Children's Hospital of Pittsburgh and the University of Pittsburgh, said in an email.

资深作者加里·科汉巴什（Gary Kohanbash）是隶属于UPMC匹兹堡儿童医院和匹兹堡大学的神经外科研究员，他在一封电子邮件中表示。

For their study, Kohanbash and colleagues in the US, Canada, Switzerland, and Israel got a look at TCR repertoires across pediatric brain cancer types by analyzing TCR alpha (TRA)- and TCR beta (TRB) gene expression with bulk RNA sequences spanning 15 major pediatric tumor histology types. They also assessed RNA-seq profiles representing peripheral blood mononuclear cell samples from 730 healthy children..

为了进行他们的研究，科哈巴什和美国、加拿大、瑞士及以色列的同事通过分析15种主要儿童肿瘤组织类型的批量RNA序列中的TCR α（TRA）和TCR β（TRB）基因表达，观察了不同儿童脑癌类型的TCR库。他们还评估了代表730名健康儿童的外周血单核细胞样本的RNA测序谱。

With these data, the team was able to dig into TCR composition and diversity within and across pediatric brain tumor types, highlighting TCR clonotypes recognizing tumor-associated antigens and tumor-specific antigens, or neoantigens, linked to mutations within the tumors.

利用这些数据，研究团队能够深入分析儿童脑肿瘤类型内部和跨类型的TCR组成和多样性，突出显示识别与肿瘤相关抗原、肿瘤特异性抗原或与肿瘤内突变相关的新生抗原的TCR克隆型。

'[O

'[O

ur research delves into the functional aspect of T-cell responses by examining clonal expansion via T-cell receptor (TCR) recombination,'

你的研究通过检查T细胞受体（TCR）重组来深入探讨T细胞反应的功能方面，特别是克隆扩增。

Kohanbash explained

科汉巴什解释了

. 'This method provides a direct measure of T-cell proliferation and activation, surpassing the limitations of gene expression or histological analyses.'

这种方法提供了T细胞增殖和激活的直接测量，超越了基因表达或组织学分析的局限性。

In particular, the investigators teased out T-cell activation and expansion patterns that they dubbed the 'clonal expansion-activation index' (CEI) — a metric that appeared to provide prognostic insights in the pediatric brain cancer cases.

特别是，研究人员揭示了他们称为“克隆扩增激活指数”（CEI）的T细胞活化和扩增模式——这一指标似乎在儿童脑癌病例中提供了预后见解。

'We show that a transcriptomic-based metric of T-cell clonality, which may imply tumor antigen-related T-cell activation and expansion, is associated with prognosis across tumor entities and subtypes,' the authors reported.

“我们展示了一个基于转录组学的T细胞克隆性指标，这可能意味着与肿瘤抗原相关的T细胞激活和扩增，与各种肿瘤实体和亚型的预后相关，”作者报告称。

While enhanced T-cell clonality and limited TCR clonotype diversity tended to track with more favorable survival outcomes, for example, the team saw ties between low CEI and relatively poor survival outcomes, suggesting T-cell clonality may provide additional information for clinicians.

虽然增强的T细胞克隆性和有限的TCR克隆类型多样性往往与更有利的生存结果相关，例如，团队观察到低CEI与相对较差的生存结果之间的联系，这表明T细胞克隆性可能为临床医生提供额外的信息。

'

'

Currently, tumor classifications are largely based on histologic and molecular features of the tumors,'

目前，肿瘤分类主要基于肿瘤的组织学和分子特征。

Kohanbash noted

科汉巴什指出

. 'We believe it is possible that quantifying clonal expansion of T cells for each patient's tumor may ultimately be an important addition to tumor classifications and inform clinicians in deciding how to best guide treatment for patients and monitor the effects of therapies, especially for immunotherapies.'.

“我们认为，量化每位患者肿瘤中T细胞的克隆扩增最终可能成为肿瘤分类的重要补充，并为临床医生决定如何最好地指导患者治疗和监测治疗效果（尤其是免疫疗法）提供信息。”

The team got a closer look at the relationship between CEI and T-cell activation and clonal expansion with follow-up experiments on five diffuse intrinsic pontine glioma, three ependymoma, and three low-grade glioma tumors, which were characterized with the help of single-cell RNA-seq and TCR-seq.

通过对五个弥漫性内生型桥脑胶质瘤、三个室管膜瘤和三个低级别胶质瘤肿瘤进行后续实验，研究团队借助单细胞 RNA 测序和 TCR 测序，进一步深入观察了 CEI 与 T 细胞活化和克隆扩增之间的关系。这些肿瘤的特征也得到了详细描述。

Beyond the potential implications for managing pediatric brain cancer cases, the researchers noted that the new findings may provide insights needed to come up with novel strategies to treat various pediatric brain tumor types based on immune features found in the tumor microenvironment, particularly for predicting tumor antigen production based on TCR features found in the tumor microenvironment..

除了对管理小儿脑癌病例的潜在影响外，研究人员指出，这些新发现可能为制定治疗各种小儿脑肿瘤类型的新策略提供所需见解，特别是基于肿瘤微环境中的免疫特征预测肿瘤抗原产生的能力，尤其是根据肿瘤微环境中发现的TCR特征进行预测。

'[I]dentification of the most promising targets remains one of the greatest challenges for personalized antigen-based immunotherapies,' Kohanbash explained. 'Our antigen discovery pipeline, while still early in development, has potential to find these promising antigens and to be continuously improved upon through the addition of new data as they become available.'.

“识别最有希望的靶点仍然是基于个性化抗原的免疫疗法面临的最大挑战之一，”科汉巴什解释道。“我们的抗原发现流程虽然仍处于早期开发阶段，但有潜力找到这些有希望的抗原，并且随着新数据的出现，通过不断添加新数据来持续改进。”

In addition to efforts aimed at validating their current findings in larger datasets encompassing still other pediatric brain tumor subtypes, he noted that members of the team are currently considering translational strategies for bringing the results to the clinic — from TCR-engineered T cells targeting antigens identified to tailored tumor-antigen immunotherapies informed by infiltrating T-cell-based antigen predictions..

除了旨在验证其当前研究结果在包含其他小儿脑肿瘤亚型的更大数据集中的努力外，他还指出，团队成员目前正在考虑将这些结果转化为临床应用的策略——从针对已识别抗原的TCR工程T细胞到基于浸润T细胞抗原预测的定制肿瘤抗原免疫疗法。