Bustos Matias A, Gross Rebecca, Rahimzadeh Negin, Cole Hunter, Tran Linh T, Tran Kevin D, Takeshima Ling, Stern Stacey L, O'Day Steven, Hoon Dave S B
Department of Translational Molecular Medicine, John Wayne Cancer Institute (JWCI), Providence Saint John's Health Center (SJHC), Santa Monica, CA 90404, USA.
Department of Immuno-Oncology and Clinical Research, JWCI, Providence SJHC, Santa Monica, CA 90404, USA.
Cancers (Basel). 2020 Nov 13;12(11):3361. doi: 10.3390/cancers12113361.
Serum lactate dehydrogenase (LDH) is a standard prognostic biomarker for stage IV melanoma patients. Often, LDH levels do not provide real-time information about the metastatic melanoma patients' disease status and treatment response. Therefore, there is a need to find reliable blood biomarkers for improved monitoring of metastatic melanoma patients who are undergoing checkpoint inhibitor immunotherapy (CII). The objective in this prospective pilot study was to discover circulating cell-free microRNA (cfmiR) signatures in the plasma that could assess melanoma patients' responses during CII. The cfmiRs were evaluated by the next-generation sequencing (NGS) HTG EdgeSeq microRNA (miR) Whole Transcriptome Assay (WTA; 2083 miRs) in 158 plasma samples obtained before and during the course of CII from 47 AJCC stage III/IV melanoma patients' and 73 normal donors' plasma samples. Initially, cfmiR profiles for pre- and post-treatment plasma samples of stage IV non-responder melanoma patients were compared to normal donors' plasma samples. Using machine learning, we identified a 9 cfmiR signature that was associated with stage IV melanoma patients being non-responsive to CII. These cfmiRs were compared in pre- and post-treatment plasma samples from stage IV melanoma patients that showed good responses. Circulating miR-4649-3p, miR-615-3p, and miR-1234-3p demonstrated potential prognostic utility in assessing CII responses. Compared to LDH levels during CII, circulating miR-615-3p levels were consistently more efficient in detecting melanoma patients undergoing CII who developed progressive disease. By combining stage III/IV patients, 92 and 17 differentially expressed cfmiRs were identified in pre-treatment plasma samples from responder and non-responder patients, respectively. In conclusion, this pilot study demonstrated cfmiRs that identified treatment responses and could allow for real-time monitoring of patients receiving CII.
血清乳酸脱氢酶（LDH）是IV期黑色素瘤患者的标准预后生物标志物。通常，LDH水平无法提供有关转移性黑色素瘤患者疾病状态和治疗反应的实时信息。因此，需要寻找可靠的血液生物标志物，以更好地监测接受检查点抑制剂免疫疗法（CII）的转移性黑色素瘤患者。这项前瞻性试点研究的目的是发现血浆中循环无细胞微小RNA（cfmiR）特征，以评估黑色素瘤患者在CII期间的反应。通过下一代测序（NGS）HTG EdgeSeq微小RNA（miR）全转录组分析（WTA；2083个miR）对47例AJCC III/IV期黑色素瘤患者和73例正常供体血浆样本在CII治疗前和治疗过程中获得的158份血浆样本中的cfmiR进行了评估。最初，将IV期无反应性黑色素瘤患者治疗前和治疗后血浆样本的cfmiR谱与正常供体血浆样本进行比较。使用机器学习，我们确定了一个9个cfmiR特征，该特征与IV期黑色素瘤患者对CII无反应相关。在显示出良好反应的IV期黑色素瘤患者的治疗前和治疗后血浆样本中对这些cfmiR进行了比较。循环miR-4649-3p、miR-615-3p和miR-1234-3p在评估CII反应中显示出潜在的预后效用。与CII期间的LDH水平相比，循环miR-615-3p水平在检测接受CII且病情进展的黑色素瘤患者方面始终更有效。通过合并III/IV期患者，在反应者和无反应者患者的治疗前血浆样本中分别鉴定出92个和17个差异表达的cfmiR。总之，这项试点研究证明了cfmiR能够识别治疗反应，并可以对接受CII的患者进行实时监测。
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