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(+) T cells and associated with an increased frequency of antigen-specific CD8(+) T cells in peripheral blood and tumors and increased antigen-specific IFN-γ 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.
Highlights
The release of extracellular ATP by phagocytes and injured or stressed cells acts as a proinflammatory coactivator of the inflammasome via P2x7 receptor signaling [1, 2]
We have recently demonstrated that CD73 expression on ER-negative mammary carcinoma cells significantly suppresses adaptive antitumor immunity and promotes tumor cell metastasis
Tumor resistance did not correlate with CD73 expression on tumor cells (Supplementary Fig. S1)
Summary
The release of extracellular ATP by phagocytes and injured or stressed cells acts as a proinflammatory coactivator of the inflammasome via P2x7 receptor signaling [1, 2]. Essentially through the enzymatic activity of CD39 (NTPDase I) and CD73 (ecto-50-nucleotidase), acts as an immunosuppressive pathway through the activation of adenosine receptors [3,4,5,6]. In the context of cancer, landmark studies by Sitkovsky and colleagues have demonstrated that the accumulation of extracellular adenosine in tumors suppresses antitumor immune responses, essentially via the activation of A2A adenosine receptors [7, 8]. Extracellular adenosine levels are generally constant in most tissue but can rapidly increase in response to hypoxia and chronic inflammation [9]. The process of extracellular adenosine accumulation in solid tumors has been recently reviewed [3]. The accumulation of extracellular adenosine in tumors generates an immunosuppressive microenvironment that effectively enhances tumor immune escape. Activation of A2A adenosine receptors on T cells has been shown to inhibit T-cell–mediated cytotoxicity, cytokine production [10] and T-cell proliferation [11, 12] and to promote T-cell anergy [13]
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