調節性髓系細胞通過代謝物丙酮醛的細胞間轉移使T細胞失活
作者：
小柯機器人發布時間：2020/4/27 13:32:51
德國慕尼黑工業大學Bastian Höchst、Percy A. Knolle等研究人員合作發現，調節性髓系細胞通過代謝物丙酮醛的細胞間轉移使T細胞失活。相關論文於2020年4月23日發表在《自然—免疫學》上。
研究人員發現，人類髓系來源抑制細胞（MDSC）的特點是代謝大大降低，並將這種受損的代謝狀態賦予CD8+T細胞，從而使其效應器功能癱瘓。研究人員鑑定到由氨基脲敏感的胺氧化酶產生的二羰基自由基丙酮醛的積累，從而引起MDSC的代謝表型和MDSC介導的CD8+T細胞失活。
在鼠類癌症模型中，二羰基活性的中和作用克服了MDSC介導的T細胞抑制作用，並與檢查點抑制作用一起改善了癌症免疫療法的功效。
因此，這些研究結果將二羰基自由基丙酮醛鑑定為MDSC的標誌代謝產物，其介導T細胞失活並且可以作為改善癌症免疫療法的靶標。
據介紹，調節性髓系免疫細胞（例如，MDSC）在發炎或癌變的組織中聚集並阻斷免疫細胞效應子的功能。人們缺乏對MDSC抑制活性的機制了解以及用於鑑定它們的標記物，因此阻礙了克服T細胞抑制和釋放抗癌免疫力的研究。
附：英文原文
Title: Regulatory myeloid cells paralyze T cells through cell–cell transfer of the metabolite methylglyoxal
Author: Tobias Baumann, Andreas Dunkel, Christian Schmid, Sabine Schmitt, Michael Hiltensperger, Kerstin Lohr, Vibor Laketa, Sainitin Donakonda, Uwe Ahting, Bettina Lorenz-Depiereux, Jan E. Heil, Johann Schredelseker, Luca Simeoni, Caroline Fecher, Nina Krber, Tanja Bauer, Norbert Hser, Daniel Hartmann, Melanie Laschinger, Kilian Eyerich, Stefanie Eyerich, Martina Anton, Matthew Streeter, Tina Wang, Burkhart Schraven, David Spiegel, Farhah Assaad, Thomas Misgeld, Hans Zischka, Peter J. Murray, Annkristin Heine, Mathias Heikenwlder, Thomas Korn, Corinna Dawid, Thomas Hofmann, Percy A. Knolle, Bastian Hchst
Issue&Volume: 2020-04-23
Abstract: Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancerous tissue and block immune cell effector functions. The lack of mechanistic insight into MDSC suppressive activity and a marker for their identification has hampered attempts to overcome T cell inhibition and unleash anti-cancer immunity. Here, we report that human MDSCs were characterized by strongly reduced metabolism and conferred this compromised metabolic state to CD8+ T cells, thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase, to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8+ T cells. In a murine cancer model, neutralization of dicarbonyl activity overcame MDSC-mediated T cell suppression and, together with checkpoint inhibition, improved the efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as a marker metabolite for MDSCs that mediates T cell paralysis and can serve as a target to improve cancer immune therapy.
DOI: 10.1038/s41590-020-0666-9
Source: https://www.nature.com/articles/s41590-020-0666-9