CD39/ENTPD1 Expression by CD4+Foxp3+ Regulatory T Cells Promotes Hepatic Metastatic Tumor Growth in Mice

Abstract

Background & Aims Adenosine mediates immune suppression and is generated by the ectonucleotidases CD39 (ENTPD1) and CD73 that are expressed on vascular endothelial cells and regulatory T cells (Treg). Although tumor-infiltrating immune cells include Foxp3+ Treg, it is not clear whether local adenosine generation by Treg promotes tumor growth in a CD39-dependent manner. In this study, we have examined the impact of CD39 expression by Treg on effector immune cell responses to hepatic metastases in vivo. Methods and Results A model of hepatic metastatic cancer was developed with portal vein infusion of luciferase-expressing melanoma B16/F10 cells and MCA38 colon cancer cells in wild type and mutant mice null for Cd39. Chimeric mice were generated by bone marrow transplantation (BMT) using Cd39 null or wild type (wt) C57BL6 donors and irradiated recipient mice. We demonstrate that hepatic growth of melanoma metastatic tumors was strongly inhibited in mice with Cd39 null vasculature or in wild type mice with circulating Cd39 null bone marrow-derived cells. We show functional CD39 expression on CD4+Foxp3+ Treg suppressed anti-tumor immunity mediated by NK cells in vitro and in vivo. Lastly, inhibition of CD39 activity by POM-1 (polyoxometalate-1), a pharmacological inhibitor of NTPDase activity, significantly inhibited tumor growth (P < .001). Conclusions CD39 expression on Treg inhibits NK activity and is permissive for metastatic growth. Pharmacological or targeted inhibition of CD39 enzymatic activity may find utility as an adjunct therapy for secondary hepatic malignancies.

Tumor-infiltrating CD39+γδTregs are novel immunosuppressive T cells in human colorectal cancer

“…Our data are consistent with the current findings that CD39 C Tregs suppress antitumor immunity, 31,48,49 and CD39 C CD8 C T cells substantially inhibit IFNg production by CD39 ¡ CD8 C T in Crohn's disease in mice via the adenosine-mediated pathway. 23 Moreover, we show that CD39 C gdTregs not only have direct immunosuppressive function on effector T cells but also secrete large amounts of IL-17A, TNF-a, and GM-CSF, which may mobilize and recruit PMN-MDSCs into the TME as we previously reported, 50 thus establishing an immunosuppressive network in CRC to promote tumor progression and metastasis.…”

A dual role for autophagy in a murine model of lung cancer

“…S13). Systemic treatment with the CD39 inhibitor polyoxometalate-1 (POM1) 46 reduces the oncogenesis-accelerating effect of autophagy deficiency without affecting the incidence of tumour initiation in autophagy-competent lung tumours (Fig. 10a,b).…”

The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27

“…In tumors, all these partners are present: (i) ATP is mainly released by dying cells and infiltrated immune cells, 12,13 (ii) CD39 and CD73 are expressed by numerous primary tumor cells 43,44 and by some infiltrating immunosuppressive cells [45][46][47][48] and (iii) adenosine receptor 2A is expressed by immune-infiltrating cells. 41 Furthermore, an accumulation of extracellular adenosine in tumor microenvironment and the subsequent purinergic signaling are involved in the regulation of immune cell functions.…”