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

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 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 resistance³. 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.