Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy

Mauro Pilato (), 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 and Thorsten R. Mempel ()
Additional contact information
Mauro Pilato: Massachusetts General Hospital
Edward Y. Kim: Massachusetts General Hospital
Bruno L. Cadilha: Massachusetts General Hospital
Jasper N. Prüßmann: Massachusetts General Hospital
Mazen N. Nasrallah: Massachusetts General Hospital
Davide Seruggia: Harvard Medical School
Shariq M. Usmani: Massachusetts General Hospital
Sandra Misale: Harvard Medical School
Valentina Zappulli: University of Padua
Esteban Carrizosa: Massachusetts General Hospital
Vinidhra Mani: Massachusetts General Hospital
Matteo Ligorio: Harvard Medical School
Ross D. Warner: Massachusetts General Hospital
Benjamin D. Medoff: Massachusetts General Hospital
Francesco Marangoni: Massachusetts General Hospital
Alexandra-Chloe Villani: Massachusetts General Hospital
Thorsten R. Mempel: Massachusetts General Hospital

Nature, 2019, vol. 570, issue 7759, 112-116

Abstract: Abstract Solid tumours are infiltrated by effector T cells with the potential to control or reject them, as well as by regulatory T (Treg) cells that restrict the function of effector T cells and thereby promote tumour growth1. The anti-tumour activity of effector T cells can be therapeutically unleashed, and is now being exploited for the treatment of some forms of human cancer. However, weak tumour-associated inflammatory responses and the immune-suppressive function of Treg cells remain major hurdles to broader effectiveness of tumour immunotherapy2. Here we show that, after disruption of the CARMA1–BCL10–MALT1 (CBM) signalosome complex, most tumour-infiltrating Treg cells produce IFNγ, resulting in stunted tumour growth. Notably, genetic deletion of both or even just one allele of CARMA1 (also known as Card11) in only a fraction of Treg cells—which avoided systemic autoimmunity—was sufficient to produce this anti-tumour effect, showing that it is not the mere loss of suppressive function but the gain of effector activity by Treg cells that initiates tumour control. The production of IFNγ by Treg cells was accompanied by activation of macrophages and upregulation of class I molecules of the major histocompatibility complex on tumour cells. However, tumour cells also upregulated the expression of PD-L1, which indicates activation of adaptive immune resistance3. Consequently, blockade of PD-1 together with CARMA1 deletion caused rejection of tumours 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 IFNγ secretion in the preferentially self-reactive Treg cell pool does not cause systemic autoimmunity but is sufficient to prime the tumour environment for successful immune checkpoint therapy.

Date: 2019
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DOI: 10.1038/s41586-019-1215-2

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