Impaired T cell and neoantigen retention in time-serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy
Cell therapy with tumor-infiltrating lymphocytes (TILs) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multidimensional analysis was performed on time-serial tumor and blood in a lung cancer TIL therapy trial. Using T cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen-specific T cell receptors. We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.
细胞疗法通过肿瘤浸润淋巴细胞（TILs）对多种癌症类型实现了持久的反应，但这种治疗方法出现耐药性的原因尚不清楚。本研究在肺癌 TIL 疗疗试验中对时间序列的肿瘤和血液样本进行了多维分析。通过对功能扩展 T 细胞以及负载抗原的四元体分选 T 细胞进行 T 细胞受体测序，我们鉴定出了肿瘤抗原特异性的 T 细胞受体。然后我们将克隆体映射到单个转录本中发现，在未见临床获益的患者中，肿瘤反应性克隆体表达了一种功能失常的程序，并缺乏类似干细胞的特征。通过跟踪肿瘤反应性克隆体在时间上的变化，我们发现抗原反应性的外围 T 细胞克隆体衰减与疾病进展的出现有关。进一步地，在疾病进展过程中，之前被输入 T 细胞靶向作用的亚克隆抗原在肿瘤中消失了，这表明可能存在适应性耐药性。我们的研究结果提示，靶向单个克隆性抗原并避免功能失常状态可能是实现 TIL 疗效的关键因素。
肿瘤(癌症)患者之家