Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center (MDACC), Houston, Texas.
Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
Clin Cancer Res. 2022 May 2;28(9):1911-1924. doi: 10.1158/1078-0432.CCR-21-1060.
Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%-50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.
We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.
Whole-exome sequencing (WES) data from 64 samples indicated a positive correlation between neoantigen load and OS, but not PFS or response to therapy. RNA sequencing analysis of 34 samples showed that expression of PDE1C, RTKN2, and NGFR was enriched in responders who had improved PFS and OS. In contrast, the expression of ELFN1 was enriched in patients with unfavorable response, poor PFS and OS, whereas enhanced methylation of ELFN1 was observed in patients with favorable outcomes. Expression of ELFN1, NGFR, and PDE1C was mainly found in cancer-associated fibroblasts and endothelial cells in tumor tissues across different cancer types in publicly available single-cell RNA sequencing datasets, suggesting a role for elements of the tumor microenvironment in defining the outcome of TIL therapy.
Our findings suggest that transcriptional features of melanomas correlate with outcomes after TIL therapy and may provide candidates to guide patient selection.
肿瘤浸润淋巴细胞（TIL）的过继细胞疗法（ACT）在转移性黑色素瘤中的反应率为 40%-50%。然而，其结果的决定因素在很大程度上尚不清楚。
我们通过研究最初用于生成 TIL 输注产品的肿瘤样本，调查了与总生存期（OS）、无进展生存期（PFS）和治疗反应相关的肿瘤相关基因组相关性。
来自 64 个样本的全外显子组测序（WES）数据表明，新抗原负荷与 OS 呈正相关，但与 PFS 或治疗反应无关。34 个样本的 RNA 测序分析表明，在 PFS 和 OS 改善的应答者中，PDE1C、RTKN2 和 NGFR 的表达得到了富集。相比之下，ELFN1 的表达在反应不良、PFS 和 OS 较差的患者中得到了富集，而在结局良好的患者中观察到 ELFN1 的甲基化增强。ELFN1、NGFR 和 PDE1C 的表达主要在肿瘤组织中的癌症相关成纤维细胞和血管内皮细胞中发现，在不同癌症类型的公开单细胞 RNA 测序数据集，提示肿瘤微环境中的某些元素可能在定义 TIL 治疗的结果中起作用。
我们的研究结果表明，黑色素瘤的转录特征与 TIL 治疗后的结果相关，并可能为指导患者选择提供候选标志物。
