GSTDTAP  > 地球科学
DOI10.1038/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
ISSN0028-0836
EISSN1476-4687
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
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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
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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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