Anti-CD73 in Cancer Immunotherapy: Awakening New Opportunities

The immune system has a critical role in the recognition and suppression of neoplastic cells. First-generation immunotherapies have been used for decades with moderate success against a few tumor types. However, most such immunotherapies display a lack of either substantial efficacy or specificity, resulting in adverse events and, thus, have limited clinical use. Over the past few years, a better understanding of the complex interactions between the immune system and tumors has allowed the identification of key molecules (i.e., CTLA-4, PD-1, and PD-L1) governing such interactions. This information has revitalized interest in cancer immunotherapeutics designed to overcome the mechanisms exploited by tumors to evade immune-mediated destruction. The complementary modes of action of novel immunotherapies and conventional chemotherapy or targeted therapy suggest the possibility for therapeutic synergy in combination treatments. Although the inhibition of CTLA-4, PD-1, or PD-L1 is being used successfully in clinical practice, additional checkpoint pathways are also being actively investigated. Among these additional pathways, ecto-5′-nucleotidase (CD73) has been found to have a critical role in driving cancer immune evasion, thus representing a promising target for the development of novel anticancer immunotherapies. Over recent years, significant advances in cancer immunotherapy have been made due to a better understanding of the principles underlying tumor biology and immunology. In this context, ecto-5′-nucleotidase (CD73) is a key molecule, because the degradation of AMP into adenosine results in the generation of an immunosuppressed and pro-angiogenic niche within the tumor microenvironment that promotes the onset and progression of cancer. Targeting CD73 has resulted in favorable antitumor effects in preclinical models, and the combined treatment of CD73 blockade with other immune-modulating agents [i.e., anti-cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibodies (mAb) or anti-programmed cell death protein (PD)-1 mAb] is a particularly attractive therapeutic option. Although there is still a long way to go, anti-CD73 therapy, through the development of CD73 mAb, could constitute a new biologic therapy for treating patients with cancer. In this review, we discuss the link between CD73 and the onset, development, and spread of tumors, highlighting the potential value of this molecule as a drug target and a novel biomarker in the context of personalized cancer therapy. Over recent years, significant advances in cancer immunotherapy have been made due to a better understanding of the principles underlying tumor biology and immunology. In this context, ecto-5′-nucleotidase (CD73) is a key molecule, because the degradation of AMP into adenosine results in the generation of an immunosuppressed and pro-angiogenic niche within the tumor microenvironment that promotes the onset and progression of cancer. Targeting CD73 has resulted in favorable antitumor effects in preclinical models, and the combined treatment of CD73 blockade with other immune-modulating agents [i.e., anti-cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibodies (mAb) or anti-programmed cell death protein (PD)-1 mAb] is a particularly attractive therapeutic option. Although there is still a long way to go, anti-CD73 therapy, through the development of CD73 mAb, could constitute a new biologic therapy for treating patients with cancer. In this review, we discuss the link between CD73 and the onset, development, and spread of tumors, highlighting the potential value of this molecule as a drug target and a novel biomarker in the context of personalized cancer therapy.