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p53是免疫逃逸的关键调节剂
作者:小柯机器人 发布时间:2020/5/20 20:31:42

美国桑福德·伯纳姆·普雷比斯医学发现研究所Robert J. Wechsler-Reya研究团队取得最新进展。他们发现肿瘤坏死因子克服了p53突变的髓母细胞瘤的免疫逃逸。2020518日的《自然-神经科学》发表了这项成果。

他们表明缺乏p53肿瘤抑制因子的髓母细胞瘤不表达表面I类主要组织相容性复合物(MHC-1),因此对免疫排斥具有抵抗力。从机理上讲,这是因为p53调节了MHC-1转运到细胞表面所必需的肽转运蛋白Tap1和氨肽酶Erap1的表达。

在体外,肿瘤坏死因子(TNF)或淋巴毒素受体激动剂可以挽救Erap1Tap1MHC-1p53突变肿瘤细胞上的表达。在体内,低剂量的TNF可以延长生存期,并与免疫检查点抑制剂协同作用以促进肿瘤排斥。

这些研究将p53鉴定为免疫逃逸的关键调节剂,并提示TNF可用于增强肿瘤对免疫疗法的敏感性。

据悉,许多免疫疗法通过增强细胞毒性T细胞杀死肿瘤细胞的能力发挥作用。杀伤取决于对肿瘤细胞上的MHC-1蛋白呈递抗原的T细胞识别。

附:英文原文

Title: Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma

Author: Alexandra Garancher, Hiromichi Suzuki, Svasti Haricharan, Lianne Q. Chau, Meher Beigi Masihi, Jessica M. Rusert, Paula S. Norris, Florent Carrette, Megan M. Romero, Sorana A. Morrissy, Patryk Skowron, Florence M. G. Cavalli, Hamza Farooq, Vijay Ramaswamy, Steven J. M. Jones, Richard A. Moore, Andrew J. Mungall, Yussanne Ma, Nina Thiessen, Yisu Li, Alaide Morcavallo, Lin Qi, Mari Kogiso, Yuchen Du, Patricia Baxter, Jacob J. Henderson, John R. Crawford, Michael L. Levy, James M. Olson, Yoon-Jae Cho, Aniruddha J. Deshpande, Xiao-Nan Li, Louis Chesler, Marco A. Marra, Harald Wajant, Oren J. Becher, Linda M. Bradley, Carl F. Ware, Michael D. Taylor, Robert J. Wechsler-Reya

Issue&Volume: 2020-05-18

Abstract: Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.

DOI: 10.1038/s41593-020-0628-4

Source: https://www.nature.com/articles/s41593-020-0628-4

期刊信息

Nature Neuroscience:《自然—神经科学》,创刊于1998年。隶属于施普林格·自然出版集团,最新if:21.126
官方网址:https://www.nature.com/neuro/
投稿链接:https://mts-nn.nature.com/cgi-bin/main.plex