Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.

中文翻译：

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黑色素瘤对 TIL 治疗临床反应的肿瘤反应性 T 细胞克隆型动力学


使用 体外扩增的肿瘤浸润淋巴细胞 （TIL） 的过继细胞疗法 （ACT） 具有不一致的临床反应。为了更好地了解治疗成功的决定因素，我们使用单细胞 RNA 和 T 细胞受体 （TCR） 测序跟踪了黑色素瘤患者从基线肿瘤到 ACT 产物以及 ACT 后血液和肿瘤样本的 TIL 克隆型。有临床反应的患者基线肿瘤富含肿瘤反应性 TIL，这些肿瘤在体外扩增时 被更有效地动员，产生富含肿瘤特异性 CD8 + 细胞的产物，这些细胞优先在 ACT 后浸润肿瘤。相反，缺乏临床反应与缺乏肿瘤反应性常驻克隆型的肿瘤以及主要由血源性克隆型组成的细胞产物相关，这些克隆型在 ACT 后在血液中持续存在，但在肿瘤中不存在。扩增后，肿瘤特异性 TILs 丢失了与肿瘤相关的转录特征，包括耗竭，反应者在肿瘤中植入 TIL 后表现出中间的耗竭效应子状态，表明功能恢复。我们的研究结果提供了对与 TIL-ACT 临床反应相关的肿瘤特异性克隆型的性质和动力学的见解，对治疗优化具有意义。