In the past years the role of the CD adenosinergic

In the past 10 years, the role of the CD73-adenosinergic pathway in suppression of anti-tumor immunity has increasingly been recognized [13], [14]. In this review, we discuss the latest findings dealing with the regulation of anti-tumor immunity by CD73 and adenosine. We also discuss ongoing clinical trials and future avenues of targeting the CD73-adenosine axis in immuno-oncology.
Conclusion
Disclosure of conflict-of-interest J. Stagg is a permanent member of the Scientific Advisory Board of Surface Oncology, holds stocks of Surface Oncology and has received research grants from Surface Oncology.
Funding support J.S. is supported by CIHR Project Grant, the Terry Fox Research Institute and the Famille Jean-Guy Sabourin Research Chair in Pharmacology of University of Montreal.
Introduction The purine ribonucleoside adenosine is an important modulator of central nervous system functions, exerting primarily inhibitory effects on neuronal activity and suppressing seizure activity in various rodent models of epilepsy [1], [2], [3]. However, traditional methods for the administration of adenosine to epileptic patients are limited by severe systemic side effects ranging from a decrease of heart rate, blood pressure, and body temperature to sedation [4]. Recently, new strategies have been developed aiming at the local administration of adenosine by intracerebral implantation of u73122 engineered to release adenosine [2], [5], [6]. Since self-renewing, totipotent embryonic stem cells (ESCs) may provide a virtually unlimited donor source for implantation, mouse ESCs were genetically engineered to lack the main adenosine-metabolizing enzyme, adenosine kinase (Adk), causing the cells to release significant amounts of adenosine [7]. These Adk deficient (Adk−/−) ESCs were subjected to a glial differentiation protocol [8] and the glial precursors could be maintained under proliferative culture conditions for several passages (>20). When allowed to differentiate, Adk−/− glial precursors were shown to mature into primarily astrocytes [7]. When encapsulated and implanted into the brain ventricle of epileptic, electrically kindled rats, the adenosine release from the Adk−/− glial precursors was effective in suppressing seizures for 5–7 days after capsule implantation at which time the cells died and seizures resumed [5]. While these studies demonstrated the effectiveness of local adenosine application for the treatment of epilepsy, they do not offer a therapeutic solution due to disadvantages associated with the material selected for encapsulation, polysulfone derivatives. One main disadvantage is the persistence of the biomaterial which may impact the viability of the encapsulated cells by causing immunogenic reactions and by eliminating activity dependent support from the host cells [9]. Furthermore, cells did not adhere to the polysulfone matrix. To address some of these challenges, protein-based biomaterials with variations related to rates of degradation were investigated in the present study. Adk−/− glial precursor growth, differentiation, and adenosine release were evaluated on fast degrading type I collagen (Col-1) substrates and slow degrading silk-fibroin (SF) substrates in comparison to poly(l-ornithine) (PO)-coated tissue culture plastic surfaces, routinely used for culture of these cells. Collagens have a longstanding tradition as biomaterial substrates for nervous tissue formation in two- [10] and three-dimensional cell culture [11]. Nerve guidance tubes based on collagen or collagen/agarose polymer blends have been used to repair segments in rat distal peripheral nerve increasing the percentage of axons crossing the anastomosis [12], [13]. However, challenges remain, mainly due to the lack of mechanical integrity and rapid degradation rates of collagens. Tubes prepared from untreated collagen were shown to separate into different layers and stenosis of the lumen occurred early after implantation, a problem which could be partly solved by cross-linking the collagen thus stabilizing the tubes [14]. However, cross-linking of collagen is associated with unwanted inflammatory potential, spontaneous and uncontrolled calcification and remaining issues concerning the rapid biodegradation within 8 weeks [15], [16], [17].