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CD73是胶质母细胞瘤的一个组合治疗靶点
作者:小柯机器人 发布时间:2019/12/25 11:19:10

美国德克萨斯大学MD安德森癌症中心Padmanee Sharma研究团队通过人类肿瘤的免疫学分析发现CD73是胶质母细胞瘤的组合治疗靶点。该研究2019年12月23日在线发表于国际一流学术期刊《自然—医学》。

为了深入了解特定于肿瘤的免疫调节靶点,研究人员分析了代表五种不同癌症类型的94位患者,包括对免疫检查点疗法反应相对较好的患者,以及对多形性胶质母细胞瘤、前列腺癌和结直肠癌没有反应的患者。通过质谱流式和单细胞RNA测序,研究人员确定了多形性胶质母细胞瘤中CD73hi巨噬细胞的独特种群,其在抗PD-1治疗后仍然存在。为了测试靶向CD73对于多形性胶质母细胞瘤的成功组合策略而言是否重要,研究人员使用CD73-/-小鼠进行了反向转化研究。研究人员发现,在抗CTLA-4和抗PD-1处理的多形性胶质母细胞瘤小鼠模型中,CD73的缺失提高了存活率。这些数据将CD73确定为一种特定的免疫治疗靶标,可改善多形性胶质母细胞瘤对免疫检查点疗法的抗肿瘤免疫反应,并证明综合性人类与反向转化研究可用于合理设计组合免疫检查点策略。

据悉,抗CTLA-4和抗PD-1/PD-L1的免疫检查点疗法彻底改变了许多实体瘤的治疗方法。但是,免疫检查点疗法的临床疗效仅限于特定肿瘤类型的患者亚组。目前正在进行组合免疫检查点策略的多项临床试验;然而,针对肿瘤特异性靶向免疫检查点的机制原理尚不清楚。

附:英文原文

Title: Immune profiling of human tumors identifies CD73 as a combinatorial target in glioblastoma

Author: Sangeeta Goswami, Thomas Walle, Andrew E. Cornish, Sreyashi Basu, Swetha Anandhan, Irina Fernandez, Luis Vence, Jorge Blando, Hao Zhao, Shalini Singh Yadav, Martina Ott, Ling Y. Kong, Amy B. Heimberger, John de Groot, Boris Sepesi, Michael Overman, Scott Kopetz, James P. Allison, Dana Peer, Padmanee Sharma

Issue&Volume: 2019-12-23

Abstract: Immune checkpoint therapy with anti-CTLA-4 and anti-PD-1/PD-L1 has revolutionized the treatment of many solid tumors. However, the clinical efficacy of immune checkpoint therapy is limited to a subset of patients with specific tumor types1,2. Multiple clinical trials with combinatorial immune checkpoint strategies are ongoing; however, the mechanistic rationale for tumor-specific targeting of immune checkpoints is elusive. To garner an insight into tumor-specific immunomodulatory targets, we analyzed 94 patients representing five different cancer types, including those that respond relatively well to immune checkpoint therapy and those that do not, such as glioblastoma multiforme, prostate cancer and colorectal cancer. Through mass cytometry and single-cell RNA sequencing, we identified a unique population of CD73hi macrophages in glioblastoma multiforme that persists after anti-PD-1 treatment. To test if targeting CD73 would be important for a successful combination strategy in glioblastoma multiforme, we performed reverse translational studies using CD73/ mice. We found that the absence of CD73 improved survival in a murine model of glioblastoma multiforme treated with anti-CTLA-4 and anti-PD-1. Our data identified CD73 as a specific immunotherapeutic target to improve antitumor immune responses to immune checkpoint therapy in glioblastoma multiforme and demonstrate that comprehensive human and reverse translational studies can be used for rational design of combinatorial immune checkpoint strategies.

DOI: 10.1038/s41591-019-0694-x

Source: https://www.nature.com/articles/s41591-019-0694-x

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex