Abstract
Extracellular adenosine is a potent endogenous immunosuppressive mediator critical to the maintenance of homeostasis in various normal tissues including the lung. Adenosine is either released from stressed or injured cells or generated from extracellular adenine nucleotides by the concerted action of the ectoenzymes ectoapyrase (CD39) and 5′ ectonucleotidase (CD73) that catabolize ATP to adenosine. An acute CD73-dependent increase of adenosine in normal tissues mostly exerts tissue protective functions whereas chronically increased adenosine-levels in tissues exposed to DNA damaging chemotherapy or radiotherapy promote pathologic remodeling processes and fibrosis for example in the skin and the lung. Importantly, cancer cells also express CD73 and high CD73 expression in the tumor tissue has been linked to poor overall survival and recurrence free survival in patients suffering from breast and ovarian cancer. CD73 and adenosine support growth-promoting neovascularization, metastasis, and survival in cancer cells. In addition, adenosine can promote tumor intrinsic or therapy-induced immune escape by various mechanisms that dampen the immune system. Consequently, modulating CD73 or cancer-derived adenosine in the tumor microenvironment emerges as an attractive novel therapeutic strategy to limit tumor progression, improve antitumor immune responses, avoid therapy-induced immune deviation, and potentially limit normal tissue toxicity. However, the role of CD73/adenosine signaling in the tumor and normal tissue responses to radiotherapy and its use as therapeutic target to improve the outcome of radiotherapy approaches is less understood. The present review will highlight the dual role of CD73 and adenosine in tumor and tissue responses to radiotherapy with a special focus to the lung. It will also discuss the potential benefits and risks of pharmacologic modulation of the CD73/adenosine system to increase the therapeutic gain of radiotherapy or combined radioimmunotherapy in cancer treatment.
Highlights
Radiotherapy is a mainstay in the treatment of cancer patients
Chemokines, or growth factors as well as upregulating specific surface receptors e.g., immunosuppressive programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated Protein 4 (CTLA4), carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), and others, tumor cells become proficient in dampening immune responses and to escape the immune system [91,92,93,94,95,96]
Dependence of Immunoglobulin Class Switch Recombination in B Cells on Vesicular Release of ATP and 5′ ectonucleotidase (CD73) Ectonucleotidase Activity Common variable immunodeficiency (CVID) patients with impaired class-switched antibody responses are selectively deficient in CD73 B cell CD73/CD39/adenosine mediates immunosuppression in DSS-induced colitis CD73 may favor cell homeostasis, memory survival, and differentiation CD73+ T cells infiltrate into breast and ovarian tumor tissue ADO induces immunosuppression CD73 expression on extracellular vesicles derived from regulatory T cells (Treg) contributes to their regulatory function CD73 expression in the lung tissue contributes to radiation-induced lung fibrosis High CD73 expression on CAFs is associated with worse prognosis
Summary
Radiotherapy is a mainstay in the treatment of cancer patients. About 60% of all cancer patients receive radiotherapy during the course of their disease alone or in multimodal combinations of surgery, radiotherapy, and chemotherapy, with beneficial effects of these highly effective treatments on long-term survival and tumor cure [1,2,3,4,5]. Further studies are needed to explore the efficacy and the safety profile of combined therapy of cancer patients suffering from thorax-associated neoplasms with radiotherapy and immunotherapies, to define biomarkers for patient selection and potential compensatory immune-tolerance mechanisms in malignant tumors [27, 67], and to define optimal treatment schedules It appears that the local induction of damage to highly radiosensitive resident cells in the lung with subsequent activation of non-targeted immune effector mechanisms might contribute to the adverse effects of ionizing radiation in normal tissues such as the development of pneumonitis and pulmonary fibrosis [68,69,70,71,72,73,74]. In the following paragraphs we will highlight the dual roles of the immune system in the response of tumor and normal tissues after irradiation that are mostly derived from pre-clinical studies
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