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CTLA-4阻断和干扰素-α对转移性黑色素瘤患者肿瘤微环境及外周血中T细胞受体库克隆性的影响。

The impact of CTLA-4 blockade and interferon-α on clonality of T-cell repertoire in the tumor microenvironment and peripheral blood of metastatic melanoma patients.

作者信息

Khunger Arjun, Rytlewski Julie A, Fields Paul, Yusko Erik C, Tarhini Ahmad A

机构信息

Department of Hematology and Oncology, Cleveland Clinic, Cleveland, OH, USA.

Adaptive Biotechnologies, Seattle, WA, USA.

出版信息

Oncoimmunology. 2019 Aug 20;8(11):e1652538. doi: 10.1080/2162402X.2019.1652538. eCollection 2019.

Abstract

Patients with metastatic melanoma were treated with tremelimumab and interferon-α (IFN) in a previously reported clinical trial [NCT00610857]. Responses were assessed by RECIST criteria as complete (CR) or partial (PR), stable disease (SD) or progressive disease (PD). In this study, T-cell receptor (TCR) beta-chain repertoire was immunosequenced in peripheral blood mononuclear cells (PBMC) specimens (N = 33) and tumor samples (N = 18) utilizing the immunoSEQ® Assay to determine repertoire clonality and T cell fractions at pre-treatment (tumor and PBMC), one month (PBMC) and 3 months (PBMC) time points and evaluate its association with clinical outcomes. In the pretreatment tumor microenvironment (TME), T cell clonality was significantly ( = .035) different and greater in patients who achieved disease control (CR, PR, SD) versus those with non-disease control (PD) as best response to treatment. Further, there was significantly ( = .001) increased TCR fraction in tissue of responders (CR, PR) versus non-responders (PD, SD). In examining T cell clonality in the circulation (PBMC), no significant associations were found in the pretreatment samples. However, early on-treatment (4 weeks) there was a significant decrease in T cell clonality that was associated with improved overall survival ( = .01) and progression-free survival ( = .04). In addition, analysis of temporal changes in tumor-infiltrating lymphocytes (TIL) and peripheral TCR repertoire revealed that responders had significantly higher clonal expansion of TIL in the circulation at 4 weeks than non-responders ( = .036). Our study provided interesting mechanistic data related to CTLA-4 Blockade and IFN and potential biomarkers of immunotherapeutic benefit.

摘要

在一项先前报道的临床试验[NCT00610857]中,转移性黑色素瘤患者接受了曲美木单抗和α干扰素(IFN)治疗。根据实体瘤疗效评价标准(RECIST)评估反应为完全缓解(CR)或部分缓解(PR)、疾病稳定(SD)或疾病进展(PD)。在本研究中,利用免疫SEQ®检测对外周血单个核细胞(PBMC)样本(n = 33)和肿瘤样本(n = 18)进行免疫测序,以确定T细胞受体(TCR)β链库,从而在治疗前(肿瘤和PBMC)、1个月(PBMC)和3个月(PBMC)时间点确定库克隆性和T细胞分数,并评估其与临床结果的关联。在治疗前的肿瘤微环境(TME)中,疾病得到控制(CR、PR、SD)的患者与疾病未得到控制(PD)的患者相比,作为对治疗的最佳反应,T细胞克隆性存在显著差异(P = 0.035)且更高。此外,反应者(CR、PR)组织中的TCR分数与无反应者(PD、SD)相比显著增加(P = 0.001)。在检查循环中(PBMC)的T细胞克隆性时,在治疗前样本中未发现显著关联。然而,在治疗早期(4周),T细胞克隆性显著降低,这与总生存期改善(P = 0.01)和无进展生存期改善(P = 0.04)相关。此外,对肿瘤浸润淋巴细胞(TIL)和外周TCR库的时间变化分析显示,反应者在4周时循环中TIL的克隆扩增显著高于无反应者(P = 0.036)。我们的研究提供了与CTLA-4阻断和IFN相关的有趣机制数据以及免疫治疗益处的潜在生物标志物。

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