In the tumor microenvironment, infiltrating effector T (Teff) cells regulate or reject cancer cells while infiltrating regulatory T (Treg) cells suppress the immune responses elicited by Teff and promote tumor progression. In our study we focused on the CARMA1–BCL10–MALT1 (CBM), a large protein cluster within immune cells that helps regulate their activation, proliferation and function. Recent research has revealed a critical role for the CBM complex in lymphocyte function and we investigated the role of CARMA1 in mouse Treg. We found that disruption of the CBM complex in all or some Tregs not only reduced their suppressive functions, but endowed them with antitumor effector functions sufficient to initiate tumor control. We observed that production of IFNγ by destabilized Tregs exclusively in the tumor microenvironment was essential and sufficient to reduce tumor growth. The increased IFNγ also triggered upregulation of PD-L1 (ligand for the T cell inhibitory receptor PD-1) and made tumors more sensitive to subsequent anti-PD1 blockade therapy. We reproduced those effects by pharmacological inhibition of CBM complex. Concretely, Mepazine (MALT1 inhibitor) induced transient tumor growth stagnation, expression PDL1 on tumor cells, and expression of IFNγ by Treg. The combination of Meapzine and anti-PD1 produced synergistic control of tumors.
Publication: Di Pilato, M.*, Kim, E.Y. Cadilha, B.L. Prüßmann, J., Nasrallah, M., Seruggia, D., Usmani, S.M. Misale, S., Zappulli, V., Carrizosa, E., Mani, V., Ligorio, M., Warner, R.D. Medoff, B.D. Marangoni, F., Villani. A.C. & Mempel, T.R. * (2019). Targeting the CBM complex causes Treg cells to prime tumors for immune checkpoint therapy, Nature 570, 112-116 * corresponding author.
doi: 10.1038/s41586-019-1215-2
Furthermore, the results of our research were emphasized by web-based medical news, newspapers and presented on International Conferences/Meetings.
