Inflammation at the site of invasive cancer has been noted since the time of Virchow (1). Chronic inflammation has been associated with contribution to tumor growth and development. Factors at a site of inflammation that contribute to tumor growth and protection are numerous. One ubiquitous factor which is under current study is adenosine. Adenosine is created by breakdown of ATP derivatives (ATP, ADP, AMP) released by hypoxia as well as necrotic cell death (2), found at the site of inflammation. Adenosine has been shown to play an immunomodulatory role at the site of inflammation on many cell types. Identification of the four adenosine receptor subtypes and their signal has aided in the understanding of how inflammation and hypoxia can alter immune function. In normal inflammation, it plays a role in initially stimulating immune infiltration but as levels increase, it suppresses an immune response due to damage to surrounding tissue (3). In cancer, the factors that contribute to the generation of adenosine are abundant and may play a role in the disruption of tumor clearance. By determining the effect of adenosine ligation of one of its inhibitory receptors, the A2a receptor (A2aR), on CD8 T-cells that mediate killing in vivo and cells that produce inflammatory or suppressive cytokines, one can determine which cells' modulation play a critical role in protecting the tumor. This project proposes to study the mechanism of A2aR that provides protection to the tumor and determine if tumor control and clearance can be improve by blocking signaling by using A2aR knock-outs (A2aR KO) and A2aR antagonists. Since the distribution of the A2aR is pervasive in cells of hematopoietic lineage, the study will also seek to improve tumor clearance by inhibiting A2aR signaling in DCs and macrophages, both which have been shown to be altered by adenosine to phenotypes similar to those observed in a cancer setting (4,5,6,7,8), phenotypes that promote tumor survival. The clinical relevance of a treatment of altering adenosine's immune suppression has the possibility to help cancer treatment and immunotherapy. Cancer treatment, via immunotherapies that try to boost the number of tumor-Ag specific effectors, has to overcome the hurdle of the immunosuppressive environment generated by the tumor and by blocking A2aR signaling, this work wishes to demonstrate the effectiveness in enhancing of an immune response by the blocking of the pervasive signal of adenosine. Blocking A2aR signaling may also improve the endogenous tumor response by boosting the generation of effectors and may also help remove a stimulus that alters DCs and macrophages into producers of anti-inflammatory cytokines. ? ? ?
