肿瘤细胞治疗研究
英文原题：Clonal expansion of resident memory T cells in peripheral blood of patients with non-small cell lung cancer during immune checkpoint inhibitor treatment.
Clonal expansion of resident memory T cells in peripheral blood of patients with non-small cell lung cancer during immune checkpoint inhibitor treatment.
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在 PBMCs 中鉴定出的一种过渡性 T 细胞亚型可能与 ICI 的持久反应相关。根据我们的研究，ICI 治疗后 PBMCs 中具有新型 TCR 的效应记忆 CD8+T 细胞的扩增可能有助于 NSCLC 患者获得更好的临床结局。这项概念验证研究加强了利用无创 PBMCs 研究 ICI 治疗相关免疫反应系统性变化的应用。
免疫检查点抑制剂（ICIs）是非小细胞肺癌（NSCLC）的重要治疗手段。目前，对ICIs应答的肿瘤相关内在因素大多已在组织样本中得到阐明。然而，组织免疫状态和免疫微环境的变化也可以通过外周血反映和监测。
使用来自60例IV期NSCLC患者的外周血单个核细胞（PBMC）进行了单细胞RNA和T细胞受体（scTCR）测序。这些样本是前瞻性采集自接受抗PD(L)-1治疗的晚期肺癌患者。根据临床结局，样本被分类为持久临床获益（DCB）和非持久临床获益（NCB）。这些样本构成配对纵向样本，包括治疗前和治疗中。此外，来自亚洲免疫多样性图谱项目的60名健康供者的PBMC样本被用作对照。
治疗前与治疗中PBMC之间主要细胞类型的动态变化与DCB组和NCB组中增殖性T细胞和NK细胞的增加相关。在T细胞亚型中，效应记忆CD8 + T细胞（CD8 + T EM _GZMK_PDCD1）在DCB组和NCB组中ICI治疗后均增加。根据谱系轨迹分析，效应记忆CD8 + T细胞位于分叉点，具有分化为前体耗竭CD8 + T细胞（CD8 + T CM细胞）谱系的潜力，推测后者与ICI反应相关。根据scTCR-seq，效应记忆CD8 + T细胞以及识别未知抗原的T细胞发生扩增，并由偏向功能障碍状态的新克隆组成，尤其是在DCB组的治疗中样本中。效应记忆CD8 + T细胞中TCR的免疫表型转化能力程度在DCB组的治疗中样本中显示出显著差异。
Immune checkpoint inhibitors (ICIs) are an essential treatment for non-small cell lung cancer (NSCLC). Currently, the tumor-related intrinsic factors in response to ICIs have mostly been elucidated in tissue samples. However, tissue immune status and changes in the immune microenvironment can also be reflected and monitored through peripheral blood.
Single-cell RNA and T cell receptor (scTCR) sequencing were conducted using peripheral blood mononuclear cells (PBMCs) from 60 patients with stage IV NSCLC. Those samples were prospectively acquired from patients treated with anti-PD(L)-1 therapy for advanced lung cancer. Based on the clinical outcomes, samples were classified as durable clinical benefit (DCB) and non-durable clinical benefit (NCB). The samples constituted paired longitudinal samples, consisting of pre-treatment and on-treatment. Additionally, PBMC samples from 60 healthy donors from the Asian Immune Diversity Atlas project were used as a control.
The dynamic changes in major cell types between pre-treatment and on-treatment PBMCs were associated with an increase in proliferating T cells and NK cells in both DCB and NCB groups. Among T cell subtypes, effector memory CD8 + T cells (CD8 + T EM _GZMK_PDCD1) were increased after ICI treatment in both DCB and NCB. From the lineage trajectory analysis, effector memory CD8 + T cells resided at the bifurcation point, which has the potential to differentiate into lineages with precursor exhausted CD8 + T cells (CD8 + T CM cells) assumed to be related to the ICI response. From the scTCR-seq, effector memory CD8 + T cells along with T cells recognizing unknown antigen expanded and composed of novel clones skewed toward dysfunctional status, especially in on-treatment samples of the DCB group. The extent of immunophenotype conversion capabilities of the TCR with effector memory CD8 + T cells showed remarkable variation in the on-treatment sample in the DCB group.
A transitioning T cell subtype identified in PBMCs might be related to the prolonged ICI response. From our study, expansion of effector memory CD8 + T cells with novel TCRs in PBMCs after ICI treatment could contribute to a better clinical outcome in patients with NSCLC. This proof-of-concept research strengthens the use of non-invasive PBMCs in studying systemic changes of immune reactions related to the ICI treatment.
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