Targeting the Immunomodulatory CD73/Adenosine System to Improve the Therapeutic Gain of Radiotherapy

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.

The CD73/Ado System—A New Player in RT Induced Adverse Late Effects

“…As opposed to this, inhibition of the low-affinity ADORA2B receptor attenuated pulmonary fibrosis induced by chronic treatment with bleomycin by repeated intraperitoneal injections [143,227] which is consistent with our findings [74,243]. Altogether these observations suggest that the beneficial or disease-promoting effects of adenosine vary depending on the tissue, the type of injury and acute vs. chronic disease stages and may be dictated by the local expression of CD73, specific adenosine receptors, or both and this might be related to local levels of tissue hypoxia [126,143,215,244].…”

“…Furthermore, chronic activation of CD73 and accumulation of adenosine were critical to the phenotypic switch of infiltrating innate and adaptive immune cells towards immunosuppressive cell types [74,243]. It is thus highly likely that RT-induced damage might also trigger release of adenosine, activation of CD73, or both, in the irradiated tumor microenvironment; hypoxia-induced or RT-induced increase in extracellular adenosine levels might then limit RT-induced immune enhancement and increase resistance to combined radioimmunotherapy by adenosine-mediated immunosuppression [42,72,244,295,333]. Intriguingly, circulating CD4 + T cells and CD4 + CD25 hi T reg of HNSCC patients including patients that had received RT as part of multimodal treatment displayed up-regulated expression of CD39 and hydrolyzed ATP at higher rates and produced higher levels of adenosine than normal controls’ T reg .…”

“…We thus propose that the CD73/adenosine signaling is an attractive therapeutic target for improving the therapeutic gain of RT: we expect that pharmacologic inhibition of CD73/adenosine signaling will not only protect irradiated tissues from early and late adverse side effects of irradiation but block at the same time tumor-promoting effects of CD73/adenosine signaling in the tumor environment and overcome CD73/adenosine-mediated tumor immune escape [42,244]. As mentioned before the expression pattern of CD39 and CD73 on immune cells (T reg , CD4 + T cells, CD8 + T cells, B cells and macrophages) differs between mice and humans.…”

CD73 blockade enhances the local and abscopal effects of radiotherapy in a murine rectal cancer model

“…Adenosine has a strong immunosuppressive property and is now considered as an important "metabolic immune checkpoint molecule" [22,34]. Inhibition of the CD73/adenosine axis attracts attention as a novel form of immunotherapy that could be combined with RT [35,36]. However, it is unclear how the modulation of adenosine levels affect the outcome of RT.…”

Purinergic Signaling in the Hallmarks of Cancer

“…As previously mentioned, ATP can also be released through P2X7R channel, and the P2X7R has been associated with the regulation of NLRP3 inflammasome, which leads to the release of pro-inflammatory cytokines, specifically IL-1β and IL-18 [26][27][28]. Importantly, antitumor therapies like chemotherapy or radiotherapy induce tissue damage and cell death and, consequently, the corresponding release of damage-associated molecular patterns (DAMPs), mainly ATP [29]. exATP is quickly converted into ADO by the CD39/CD73 pathway, establishing a particular proportion of purines in the TME where both purines can potentially affect cancer and host cells; this equilibrium is decisive for the outcome of a given clinical treatment [30].…”