Targeting T_reg cells

Nature https://doi.org/10.1038/s41586-019-1215-2 (2019)

The immunosuppressive function of regulatory T cells (T_reg cells) counteracts the effectiveness of tumor immunotherapy. In Nature, Mempel and colleagues show that disruption of the CARMA1–BCL10–MALT1 signalosome complex in T_reg cells leads to production of the cytokine IFN-γ in these cells and the initiation of tumor control. Homozygous deletion of Carma1 in T_reg cells (via Foxp3-Cre) in mice results in T_reg cell secretion of IFN-γ and multi-organ inflammation, but heterozygous deletion does not, whereas both homozygous tumor-infiltrating CARMA1-deficient T_reg cells and their heterozygous counterparts secrete IFN-γ and are sufficient to diminish tumor growth. Acute deletion of CARMA1 in T_reg cells reduces growth in already established tumors, and both constitutive deletion and acute deletion of CARMA1 in T_reg cells trigger expression of the inhibitory ligand PD-L1 on tumor cells. Inhibitors of the paracaspase activity of MALT1 have effects similar to those of the T_reg cell deletion of CARMA1 and act in synergy with treatment with antibody to the inhibitory receptor PD-1 to induce tumor control and relapse-free rejection in checkpoint blockade–resistant tumors.