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DOI | 10.1038/s41586-019-1254-8 |
Targeting the CBM complex causes T-reg cells to prime tumours for immune checkpoint therapy | |
Di Pilato, Mauro1,2; Kim, Edward Y.1,2; Cadilha, Bruno L.1; Prussmann, Jasper N.1,2; Nasrallah, Mazen N.1,2; Seruggia, Davide2,3; Usmani, Shariq M.1,2; Misale, Sandra2,4; Zappulli, Valentina5; Carrizosa, Esteban1,2; Mani, Vinidhra1,2; Ligorio, Matteo2,4; Warner, Ross D.1; Medoff, Benjamin D.1,2; Marangoni, Francesco1,2; Villani, Alexandra-Chloe1,2; Mempel, Thorsten R.1,2 | |
2019-06-05 | |
发表期刊 | NATURE
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ISSN | 0028-0836 |
EISSN | 1476-4687 |
出版年 | 2019 |
卷号 | 570期号:7759页码:112-+ |
文章类型 | Article |
语种 | 英语 |
国家 | USA; Italy |
英文摘要 | Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (T-reg) cells that restrict the function of effector T cells and thereby promote tumour growth1. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of T-reg cells remain major hurdles to broader effectiveness of tumour immunotherapy2. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating T-reg cells produce IFN gamma, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of T-reg cells-which avoided systemic autoimmunity-was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by T-reg cells that initiates tumour control. The production of IFN gamma by Treg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance(3). Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours that otherwise do not respond to anti-PD-1 monotherapy. This effect was reproduced by pharmacological inhibition of the CBM protein MALT1. Our results demonstrate that partial disruption of the CBM complex and induction of IFN gamma secretion in the preferentially self-reactive T-reg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy. |
领域 | 地球科学 ; 气候变化 ; 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000470149000049 |
WOS关键词 | PD-1 BLOCKADE ; MALT1 PROTEASE ; EFFECTOR ; CARMA1 ; REQUIREMENT ; SENSITIVITY ; ACTIVATION ; INHIBITORS ; RESPONSES ; SIGNALS |
WOS类目 | Multidisciplinary Sciences |
WOS研究方向 | Science & Technology - Other Topics |
URL | 查看原文 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/203067 |
专题 | 地球科学 资源环境科学 气候变化 |
作者单位 | 1.Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Boston, MA 02114 USA; 2.Harvard Med Sch, Boston, MA 02115 USA; 3.Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA; 4.Massachusetts Gen Hosp, Ctr Canc Res, Boston, MA 02114 USA; 5.Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy |
推荐引用方式 GB/T 7714 | Di Pilato, Mauro,Kim, Edward Y.,Cadilha, Bruno L.,et al. Targeting the CBM complex causes T-reg cells to prime tumours for immune checkpoint therapy[J]. NATURE,2019,570(7759):112-+. |
APA | Di Pilato, Mauro.,Kim, Edward Y..,Cadilha, Bruno L..,Prussmann, Jasper N..,Nasrallah, Mazen N..,...&Mempel, Thorsten R..(2019).Targeting the CBM complex causes T-reg cells to prime tumours for immune checkpoint therapy.NATURE,570(7759),112-+. |
MLA | Di Pilato, Mauro,et al."Targeting the CBM complex causes T-reg cells to prime tumours for immune checkpoint therapy".NATURE 570.7759(2019):112-+. |
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