Targeting the CBM complex causes T.sub.reg cells to prime tumours for immune checkpoint therapy

• Published in: Nature (London) 2019-06, Vol.570 (7759), p.112
• Main Authors: Di Pilato, Mauro, Kim, Edward Y, Cadilha, Bruno L, Prüßmann, Jasper N, Nasrallah, Mazen N, Seruggia, Davide, Usmani, Shariq M
• Format: Article
• Language: English
• Subjects: Care and treatment; Genetic aspects; Health aspects; Immunotherapy; Observations; T cells; Tumors
• 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.sub.reg) cells that restrict the function of effector T cells and thereby promote tumour growth.sup.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.sub.reg cells remain major hurdles to broader effectiveness of tumour immunotherapy.sup.2. Here we show that, after disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, most tumour-infiltrating T.sub.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.sub.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.sub.reg cells that initiates tumour control. The production of IFN[gamma] by T.sub.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.sup.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.sub.reg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy.