Skip to main content
European Commission logo print header

Neutrophil subtypes: distinct cellular targets for therapeutic intervention

Periodic Reporting for period 2 - TANTUMorNEUVACCINE (Neutrophil subtypes: distinct cellular targets for therapeutic intervention)

Reporting period: 2019-10-01 to 2020-09-30

Many patients with tumors do not respond to immune therapies - such as anti-PD-1 immune checkpoint blockade - because of a lack of pre-existing inflammation that is required for those therapies to work. We decided to reprogram regulatory T cells (Treg) specifically in tumors to provide exactly the type of inflammation that is lacking. Indeed, we turn immunosuppressive tumor-infiltrating Treg cells in pro-inflammatory agents that promote tumor rejection without causing autoimmunity. Secretion of inflammatory cytokines by Treg makes those previously unresponsive tumors highly sensitive to anti PD-1 blockade.
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.