Targeting the CBM Complex Causes Treg Cells to Prime Tumours for Immune Checkpoint Therapy
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CitationDi Pilato, Mauro, Edward Y. Kim, Bruno L. Cadilha, Jasper N. Prüßmann, Mazen N. Nasrallah, Davide Seruggia, Shariq M. Usmani, Sandra Misale, Valentina Zappulli, Esteban Carrizosa, Vinidhra Mani, Matteo Ligorio, Ross D. Warner, Benjamin D. Medoff, Francesco Marangoni, Alexandra-Chloe Villani & Thorsten R. Mempel. 2019. Targeting the CBM Complex Causes Treg Cells to Prime Tumours for Immune Checkpoint Therapy. Nature 570, no. 7759: 112-116.
AbstractSolid tumors are infiltrated by effector T cells (Teff) with the potential to control or reject them, as well as by regulatory T cells (Treg) that restrict the function of Teff and thereby promote tumor growth.1 The anti-tumor activity of Teff can be therapeutically unleashed and is now being exploited for the treatment of some forms of human cancer. However, weak tumor-associated inflammatory responses and the immune-suppressive function of Treg remain major hurdles to broader effectiveness of tumor immunotherapy.2 Here we show that upon disruption of the CARMA1-BCL10-MALT1 (CBM) signalosome complex, the majority of tumor-infiltrating Treg produce IFN-, followed by stunted tumor growth. Remarkably, genetic deletion of both or even just one allele of CARMA1 in only a fraction of Treg, which avoided systemic autoimmunity, was sufficient to produce this anti-tumor effect, showing that not mere loss of suppressive function, but gain of effector activity by Treg initiates tumor control. Treg-production of IFN- was accompanied by macrophage activation and up-regulation of MHC-I on tumor cells. However, tumor cells also up-regulated expression of PD-L1, indicating activation of adaptive immune resistance.3 Consequently, PD-1 blockade concomitant with CARMA1-deletion caused rejection of tumors 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--secretion in the preferentially self-reactive Treg pool does not cause systemic autoimmunity but is sufficient to prime the tumor environment for successful immune checkpoint therapy.
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