Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy

• Published in: Nature (London) Vol. 570; no. 7759; pp. 112 - 116
• Main Authors: Di Pilato, Mauro, Kim, Edward Y., Cadilha, Bruno L., Prüßmann, Jasper N., Nasrallah, Mazen N., Seruggia, Davide, Usmani, Shariq M., Misale, Sandra, Zappulli, Valentina, Carrizosa, Esteban, Mani, Vinidhra, Ligorio, Matteo, Warner, Ross D., Medoff, Benjamin D., Marangoni, Francesco, Villani, Alexandra-Chloe, Mempel, Thorsten R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.06.2019; Nature Publishing Group
• Subjects: 13/31; 13/51; 13/95; 45/41; 45/77; 45/91; 631/250/251; 631/67/580; 64/60; 82/1; 96/21; 96/35; Anticancer properties; Antigens; Autoimmunity; Bcl-10 protein; Cancer; Cell activation; Clonal deletion; Cytokines; Disruption; Effector cells; Gene expression; Homeostasis; Humanities and Social Sciences; Immune checkpoint; Inflammation; Inflammatory diseases; Letter; Lymphocytes; Lymphocytes T; Macrophages; Major histocompatibility complex; Melanoma; multidisciplinary; PD-1 protein; PD-L1 protein; Pharmacology; Proteins; Science; Science (multidisciplinary); Solid tumors; Therapy; Transcription factors; Tumors; γ-Interferon
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1215-2

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 growth 1 . 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 immunotherapy 2 . Here we show that, after disruption of the CARMA1–BCL10–MALT1 (CBM) signalosome complex, most tumour-infiltrating T reg cells produce IFNγ, 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 IFNγ by T reg 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 IFNγ 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. Disruption of the CARMA1–BCL10–MALT1 (CBM) signalosome causes T reg cells to produce IFNγ and develop dominant anti-tumour activity in synergy with anti-PD-1 treatment, and in the absence of autoimmunity.