Person:
Usmani, Shariq

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Usmani

First Name

Shariq

Name

Usmani, Shariq

Filters

20191

Settings

Author's Publications: search.filters.isAuthorOfPublication.31fcfd46-2e99-4532-a547-62df043a52c2

Search Results

Now showing 1 - 1 of 1
  • No Thumbnail Available
    Publication
    Targeting the CBM Complex Causes Treg Cells to Prime Tumours for Immune Checkpoint Therapy
    (Springer Science and Business Media LLC, 2019-05-15) Di Pilato, Mauro; Ligorio, Matteo; Kim, Edward; Cadilha, Bruno; Prüßmann, Jasper; Nasrallah, Mazen; Seruggia, Davide; Usmani, Shariq; Misale, Sandra; Zappulli, Valentina; Carrizosa, Esteban; Mani, Vinidhra; Warner, Ross; Medoff, Benjamin; Marangoni, Francesco; Villani, Alexandra-Chloe; Mempel, Thorsten
    Solid 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.