CD73-Deficient Mice Have Increased Antitumor Immunity and Are Resistant to Experimental Metastasis

Abstract

CD73 is a cell-surface enzyme that suppresses immune responses by producing extracellular adenosine. In this study, we employed CD73 gene-targeted mice to investigate the role of host-derived CD73 on antitumor immunity and tumor cell metastasis. We found that CD73 ablation significantly suppressed the growth of ovalbumin-expressing MC38 colon cancer, EG7 lymphoma, AT-3 mammary tumors, and B16F10 melanoma. The protective effect of CD73 deficiency on primary tumors was dependent on CD8 þ T cells and associated with an increased frequency of antigen-specific CD8 þ T cells in peripheral blood and tumors and increased antigenspecific IFN-g production. Replicate studies in bone marrow chimeras established that both hematopoietic and nonhematopoietic expression of CD73 was important to promote tumor immune escape. Using adoptive reconstitution of T regulatory cell (Treg)-depleted DEREG (depletion of regulatory T cells) mice, we demonstrated that part of the protumorigenic effect of Tregs was dependent on their expression of CD73. CD73-deficient mice were also protected against pulmonary metastasis of B16F10 melanoma cells after intravenous injection. Unexpectedly, we found that the prometastatic effect of host-derived CD73 was dependent on CD73 expression on nonhematopoietic cells. CD73 expression on nonhematopoietic cells, most likely endothelial cells, was critical for promoting lung metastasis in a manner independent from immunosuppressive effects. Notably, in vivo blockade of CD73 with a selective inhibitor or anti-CD73 monoclonal antibody significantly reduced tumor growth and metastasis of CD73-negative tumors. Taken together, our findings indicate that CD73 may be targeted at multiple levels to induce anticancer effects including at the level of tumor cells, Tregs, and nonhematopoietic cells. Cancer Res; 71(8); 2892-900. Ó2011 AACR.

NTPDase3 and ecto-5′-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression

“…This result is in agreement with the literature that shows the increase of ecto-5′-NT/CD73 expression in many other cancers such as breast cancer, glioma, and melanoma [19,23,56]. Furthermore, ecto-5′-NT/CD73 overexpression promotes invasion, migration, adhesion, and metastasis of human breast cancer cells [20,57], indicating higher invasiveness and metastatic capability to melanomas [56,58] and poor prognosis in human colorectal cancer [22]. Ecto-5′-NT/CD73 expression in cancer cells has been also linked with drug resistance [26,59] and immune escape [44,60].…”

Adenosine arrests breast cancer cell motility by A3 receptor stimulation

“…Stagg et al and Zhou et al found that CD73, the ectoenzyme responsible for endogenous adenosine formation, contributes to breast cancer metastasis [15][16][17]. In agreement with these reports, we found that MDA-MB-231 cells overexpress CD73 and differ from HMEC in that they possess more efficient means than HMEC to hydrolyze extracellular ATP to adenosine (Fig.…”

“…Similarly, the ATP breakdown product adenosine can activate calcium signaling in MDA-MB-231 breast cancer cells, and the ectonucleotidase C D 7 3 , w h i c h c o n v e r t s e x t r a c e l l u l a r a d e n o s i n e monophosphate (AMP) to adenosine, was shown to promote breast cancer growth and metastasis [15][16][17]. In light of our previous work, these reports support the concept that purinergic signaling can indeed contribute to the motility and metastasis of breast cancer cells.…”

Potential prognostic biomarker CD73 regulates epidermal growth factor receptor expression in human breast cancer

“…Other groups also reported the association between CD73 expression and metastasis in breast cancer cell lines and CD73-/-mice (20). In this study, we further explored the clinical significance and potential mechanisms of CD73 in breast cancer by IHC on TMAs.…”

“…Adenosine, acting through G-protein coupled receptors, plays an important role not only in immune suppression but also in malignant behavior of tumor cells (18). CD73-deficient mice are resistant to the development of 3-methylcholanthrene (MCA)-induced fibrosarcomas through a mechanism relying on IFN-c, natural killer (NK) cells, and CD81 T cells (19), while treatment with a selective inhibitor a,b-methylene ADP (APCP) or anti-CD73 monoclonal antibody significantly reduced tumor growth and metastasis (20). Although many of the CD73 effects are consequences of its adenosine production, also more direct interactions have been reported.…”