血清 CD73 是转移性黑色素瘤患者的预后因素，与抗 PD-1 治疗的反应相关。

Serum CD73 is a prognostic factor in patients with metastatic melanoma and is associated with response to anti-PD-1 therapy.

机构信息

Pharmacy, University of Salerno, Fisciano, Campania, Italy.

PhD Program in Drug Discovery and Development, University of Salerno, Fisciano, Campania, Italy.

出版信息

J Immunother Cancer. 2020 Dec;8(2). doi: 10.1136/jitc-2020-001689.

DOI:10.1136/jitc-2020-001689

PMID:33361405

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7759961/

Abstract

BACKGROUND

Inhibitors of immune checkpoint programmed cell death protein 1 (PD-1) receptor on T cells have shown remarkable clinical outcomes in metastatic melanoma. However, most patients are resistant to therapy. Production of extracellular adenosine, via CD73-mediated catabolism of AMP, contributes to suppress T-cell-mediated responses against cancer. In this study, we analyzed the expression and activity of soluble CD73 in sera of patients with melanoma undergoing anti-PD-1± cytotoxic T-lymphocyte-associated antigen 4 therapy.

METHODS

Soluble CD73 expression and activity were retrospectively analyzed in serum of a total of 546 patients with melanoma from different centers before starting treatment (baseline) with anti-PD-1 agents, nivolumab or pembrolizumab, and compared with those of 96 healthy subjects. The CD73 activity was correlated with therapy response and survival of patients.

RESULTS

Patients with melanoma show significantly higher CD73 activity and expression than those observed in healthy donors (p<0.0001). Elevated pretreatment levels of CD73 activity were associated with non-response to therapy with nivolumab or pembrolizumab. During treatment, levels of soluble CD73 activity remain unchanged from baseline and still stratify clinical responders from non-responders. High levels of serum CD73 enzymatic activity associate with reduced overall survival (OS; HR=1.36, 95% CI 1.03 to 1.78; p=0.03) as well as progression-free survival (PFS; HR=1.42, 95% CI 1.13 to 1.79, p=0.003). Further, the multivariate Cox regression analysis indicates that serum CD73 activity is an independent prognostic factor besides serum lactate dehydrogenase levels and the presence of brain metastases for both OS (p=0.009) and PFS (p=0.001).

CONCLUSION

Our data indicate the relevance of serum CD73 in patients with advanced melanoma receiving anti-PD-1 therapy and support further investigation on targeting CD73 in combination with anti-PD-1 antibodies.

摘要

背景

T 细胞程序性死亡蛋白 1（PD-1）受体的免疫检查点抑制剂在转移性黑色素瘤中显示出显著的临床疗效。然而，大多数患者对治疗有耐药性。细胞外腺苷的产生，通过 CD73 介导的 AMP 分解代谢，有助于抑制 T 细胞介导的抗癌反应。在这项研究中，我们分析了接受抗 PD-1±细胞毒性 T 淋巴细胞相关抗原 4 治疗的黑色素瘤患者血清中可溶性 CD73 的表达和活性。

方法

回顾性分析了来自不同中心的 546 例黑色素瘤患者在开始接受抗 PD-1 药物（nivolumab 或 pembrolizumab）治疗前（基线）的血清可溶性 CD73 表达和活性，并与 96 例健康受试者进行比较。CD73 活性与患者的治疗反应和生存相关。

结果

与健康供体相比，黑色素瘤患者的 CD73 活性和表达显著升高（p<0.0001）。治疗前 CD73 活性升高与 nivolumab 或 pembrolizumab 治疗无反应相关。在治疗过程中，血清可溶性 CD73 活性从基线水平保持不变，仍然将临床应答者与无应答者区分开来。高水平的血清 CD73 酶活性与总生存（OS；HR=1.36，95%CI 1.03 至 1.78；p=0.03）和无进展生存（PFS；HR=1.42，95%CI 1.13 至 1.79，p=0.003）相关。此外，多变量 Cox 回归分析表明，血清 CD73 活性是除血清乳酸脱氢酶水平和脑转移存在外，OS（p=0.009）和 PFS（p=0.001）的独立预后因素。