Epithelial cell adhesion molecule (EpCAM) is a tumor-associated antigen that is frequently overexpressed in various carcinomas. We have developed chimeric antigen receptor (CAR) T cells specifically targeting EpCAM for the treatment of gastric cancer. This study sought to unravel the precise mechanisms by which tumors evade immune surveillance and develop resistance to CAR T cell therapy. Through a combination of whole-body CAR T cell imaging and single-cell multiomic analyses, we uncovered intricate interactions between tumors and tumor-infiltrating lymphocytes (TILs). In a gastric cancer model, tumor-infiltrating CD8 T cells exhibited both cytotoxic and exhausted phenotypes, while CD4 T cells were mainly regulatory T cells. A T cell receptor (TCR) clonal analysis provided evidence of CAR T cell proliferation and clonal expansion within resistant tumors, which was substantiated by whole-body CAR T cell imaging. Furthermore, single-cell transcriptomics showed that tumor cells in mice with refractory or relapsing outcomes were enriched for genes involved in major histocompatibility complex (MHC) and antigen presentation pathways, interferon-γand interferon-αresponses, mitochondrial activities, and a set of genes (e.g.,CD74,IDO1,IFI27) linked to tumor progression and unfavorable disease prognoses. This research highlights an approach that combines imaging and multiomic methodologies to concurrently characterize the evolution of tumors and the differentiation of CAR T cells.
上皮细胞黏附分子（EpCAM）是一种肿瘤相关抗原，在多种癌组织中常出现过表达现象。本研究开发了特异性靶向EpCAM的嵌合抗原受体（CAR）T细胞用于胃癌治疗，旨在揭示肿瘤逃避免疫监视及产生CAR T细胞治疗耐药性的精确机制。通过全身CAR T细胞成像与单细胞多组学分析相结合的方法，我们揭示了肿瘤与肿瘤浸润淋巴细胞（TILs）之间复杂的相互作用。在胃癌模型中，肿瘤浸润性CD8 T细胞同时表现出细胞毒性表型和耗竭表型，而CD4 T细胞主要为调节性T细胞。T细胞受体（TCR）克隆分析证实了耐药肿瘤内存在CAR T细胞增殖和克隆扩增现象，这一发现通过全身CAR T细胞成像得到进一步验证。单细胞转录组学分析显示，在治疗无效或复发的小鼠模型中，肿瘤细胞中主要组织相容性复合体（MHC）与抗原呈递通路相关基因、干扰素-γ与干扰素-α应答基因、线粒体活性相关基因，以及与肿瘤进展和不良预后相关的一组基因（如CD74、IDO1、IFI27）均呈现富集状态。本研究展示了一种整合成像技术与多组学方法的研究策略，可同步表征肿瘤演化过程与CAR T细胞分化轨迹。
肿瘤(癌症)患者之家