1. Something in the Air: Hyperoxic Conditioning of the Tumor Microenvironment for Enhanced Immunotherapy 
Robert D. Leone, Maureen R. Horton, Jonathan D. Powell 
Cancer Cell 
Volume 27, Issue 4, Pages (April 2015)
DOI: /j.ccell
Copyright © 2015 Elsevier Inc. Terms and Conditions

2. Figure 1 The Hypoxia-Adenosinergic Pathway in Immune Regulation
Partially through stabilization of HIF-1α, hypoxia in inflamed and cancerous tissues drives the intracellular accumulation of adenosine by causing decreased ATP and adenosine kinase (AK) activity as well as increasing intracellular AMP and 5′-nucleotidase activity (5′N). Additionally, HIF-1α activity drives increased expression of the 5′-ectonucleotidases CD39 and CD73, which are transmembrane proteins that catalyze the enzymatic breakdown of ATP to adenosine. Both of these mechanisms lead to significant elevation of extracellular adenosine concentrations in the microenvironment. Signaling through two Gs-protein-coupled adenosine receptors (A2aR and A2bR), adenosine triggers an increase in the intracellular signaling molecule cyclic AMP (cAMP). Within immune effector cells such as cytotoxic T cells and NK cells, cAMP causes a buildup of a range of immunosuppressive factors (TGF-β, IL-10, CTLA-4, PD-1, Galectin-1, FoxP3), as well as the downregulation of key effector molecules (IL-2, INF-γ, TNF-α, perforin, IL-12, MIP1α) involved in an active immune response. A2aR, adenosine A2a receptor; A2bR, adenosine A2b receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; FoxP3, forkhead box P3; HIF1-α, hypoxia inducible factor-1α; INFγ, interferon-γ; IL-2, interleukin-2; IL-10, interleukin-10; IL-12, interleukin-12; MIP1α, macrophage inflammatory protein 1α; PD-1, programmed cell death protein 1; TGF-β, transforming growth factor-β; TNFα, tumor necrosis factor-α.
Cancer Cell  , DOI: ( /j.ccell )
Copyright © 2015 Elsevier Inc. Terms and Conditions