Abstract
CD73 is a cell surface 5'-nucleotidase that converts AMP to adenosine, an immune suppressive molecule. CD73 may promote immune escape in cancer by contributing to the degradation of extracellular ATP released by dying cancer cells in hypoxic tumors or following chemotherapy. However, whether CD73 exerts a critical oncogenic function during tumorigenesis is unknown. In this study, we used genetically deficient mice to investigate its contribution to autochthonous tumor formation. CD73 deficiency suppressed the development of 3-methylcholanthrene (MCA)-induced fibrosarcomas through a mechanism relying upon IFN-γ, natural killer (NK) cells, and CD8(+) T cells. Similarly, CD73 deficiency also suppressed prostate tumorigenesis in TRAMP transgenic mice. Importantly, treatment with an anti-CD73 monoclonal antibody effectively suppressed growth of established MCA-induced tumors or TRAMP-C1 prostate tumors and inhibited the development of TRAMP-C1 lung metastases. The therapeutic activity of anti-CD73 monoclonal antibody against primary tumors was dependent on CD8(+) T cells, whereas its antimetastatic activity was dependent on host CD73 expression independent of T cells or NK cells. Taken together, our findings indicate that CD73 is a critical factor in tumorigenesis and that anti-CD73 antibodies may offer a novel generalized strategy to blunt immune escape and treat cancer.
Highlights
The tumor microenvironment is an important regulator of immune functions that impact cancer progression and metastasis
Landmark studies by Sitkovsky and colleagues have shown that accumulation of extracellular adenosine in tumors suppresses antitumor immune responses, essentially via the activation of A2A adenosine receptors [4,5,6]
We assessed the importance of CD73 in the MCA induction model of fibrosarcoma, in which host immunity plays a critical factor in suppressing tumor initiation and progression
Summary
The tumor microenvironment is an important regulator of immune functions that impact cancer progression and metastasis. We and others have recently shown that one of the mechanisms contributing to the immunosuppressive accumulation of extracellular adenosine in tumors is the expression of CD73 by tumor cells [11, 12]. These studies revealed that CD73 expression on breast cancer and ovarian cancer cells significantly suppress adaptive antitumor immunity. Host CD73 has been shown to protect against acute graft versus host disease and to inhibit graft versus leukaemia effect [17] Taken together, these studies suggest that CD73 may be a valid therapeutic target to enhance antitumor immunity. We here investigated the role of CD73 on de novo tumorigenesis
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