Our group and others have previously reported that Treg infiltrating (Ti-Treg) breast tumors have a negative impact on patients’ outcome. We further reported their selective recruitment in the tumor environment through CCL22 secretion and expansion upon ICOS engagement by plasmacytoïd dendritic cells.
Here, we investigated the mechanism of Ti-Treg mediated suppression and observed that Ti-Treg express high CD39 levels. CD39 is an ectonucleotidase that cooperates with CD73 to degrade the danger signal ATP into immunosuppressive Adenosine (Ado). The potency of Ado mediated suppression is illustrated in Adenosine-Deaminase (ADA)-deficient patients unable to degrade Ado and developing severe immunodeficiency.
We further show that, in contrast to murine Treg, human CD39+Treg do not express CD73 enabling them only to degrade ATP into AMP. Within T cells, CD73 expression was mainly associated with naïve CD8+ T cells and a subset of memory conventional CD4+ T cells (Tconv) that exhibit Th1/Th17 characteristics (CXCR3+CCR6+CCR4negIFNγhighIL17+). CD39+ Treg isolated from healthy donor blood, in presence of exogenous ATP, potently inhibit purified CD73+ but not CD73neg Tconv, proliferation and cytokine production (IFNγ, TNFα). By using enzymatic inhibitors, we demonstrated the involvement of CD39 and CD73 through Treg/Tconv cooperation for Ado mediated immunosuppression. Of importance, when integrated in [Treg-CD4+CD73+] high density coculture, CD4+CD73neg T cells expressing similar levels of Ado receptors (A2A, A2B) are also inhibited.
In conclusion, our findings support the existence of an Ado mediated immunosuppression loop in the tumor through cooperation between CD39highTreg and CD73-expressing Th1/Th17 subsets in the breast tumor environment.
The research leading to these results has received funding from the European Community's Seventh Framework Program (FP7/2007-2013) under grant agreement n°602200.
Citation Format: Nicolas Gourdin, Céline Rodriguez, Selena Vigano, Isabelle Durand, Julien Faget, Camilla Jandus, Jean Yves Blay, Pedro Romero, Christine Menetrier-Caux, Christophe Caux. CD39+ Treg cooperate with a CD73-expressing Th1/Th17 subset for Adenosine-mediated immunosuppression in human breast tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2338.