TY - JOUR
T1 - Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy
AU - Di Pilato, Mauro
AU - Kim, Edward Y.
AU - Cadilha, Bruno L.
AU - Prüßmann, Jasper N.
AU - Nasrallah, Mazen N.
AU - Seruggia, Davide
AU - Usmani, Shariq M.
AU - Misale, Sandra
AU - Zappulli, Valentina
AU - Carrizosa, Esteban
AU - Mani, Vinidhra
AU - Ligorio, Matteo
AU - Warner, Ross D.
AU - Medoff, Benjamin D.
AU - Marangoni, Francesco
AU - Villani, Alexandra Chloe
AU - Mempel, Thorsten R.
N1 - Funding Information:
Acknowledgements We thank the MGH Pathology Flow Cytometry Core and N. Ali-Akbar for technical assistance. This study was funded by an EMBO fellowship (ALTF534-2015) and a Marie Curie Global Fellowship (750973) (M.D.P.), DFG Fellowships (PR 1652/1-1 to J.N.P and US 116/2-1 to S.M.U), NIH T32 CA207021 (V.M.), a Sara Elizabeth O’Brien Fellowship (F.M.), and Melanoma Research Alliance Senior Investigator Award MRA-348693, NIH AI123349, and the Bob and Laura Reynolds MGH Research Scholar Award (T.R.M.).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/6/6
Y1 - 2019/6/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065981893&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85065981893&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1215-2
DO - 10.1038/s41586-019-1215-2
M3 - Article
C2 - 31092922
AN - SCOPUS:85065981893
SN - 0028-0836
VL - 570
SP - 112
EP - 116
JO - Nature
JF - Nature
IS - 7759
ER -