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Footnotes ?1 Abbreviations: PDE, phosphodiesterase; cAMP, adenosine 3?5?-cyclic monophosphate; cGMP, guanosine 3?5?-cyclic monophosphate; GAF, cyclic GMP, adenylyl cyclase, FhlA; CaM, calmodulin; PK, protein kinase; PKA, cAMP-dependent protein kinase; PKG, cGMP-dependent protein kinase; CNS, central nervous system; ANP, atrial natriuretic peptide; NO, nitric oxide; PDP, 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one; BAY 60-7750, 2-(3,4-dimethoxybenzyl)-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methylimidazo[5,1-f] [1,2,4]triazin-4(3H)-one; PI3K, phosphatidylinositol 3-kinase; IGF1, insulin-like growth factor 1; OPC-33450, 6-[3-[3-cyclooctyl-3-[(1R*,2R*)-2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone; UCR, upstream conserved region; CRE, cAMP-responsive element-binding protein; RACK, receptor for activated C-kinase 1; AKAP, A-kinase anchoring proteins; ERK, extracellular signal-regulated kinase; BRL 50481, 3-(N,N-dimethylsulfonamido)-4-methyl-nitrobenzene; PAS, Period, Arnt, and Sim; IBMX, 3-isobutyl-1-methylxanthine; BAY 73-6691, 1-(2-chlorophenyl)-6-[(2R)-3,3,3-trifluoro-2-methylpropyl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one.
Extensive data exist in mouse models correlating tumor progression with the accumulation of myeloid inhibitory cells such as CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) (4), immature dendritic cells (5), and F4/80+ macrophages (6) that induce local and possibly systemic immunosuppression (7). L-Arginine metabolism is an important pathway used by MDSCs to blunt antitumor immunity (8). In these cells, arginase-1 (ARG1) and nitric oxide synthase–2 (NOS2), the key enzymes in L-arginine catabolism, work either alone or synergistically to suppress T cell function (9). The elimination, functional inhibition, or differentiation of MDSCs in tumor-bearing hosts can restore CD8+ T cell responsiveness (10, 11), thereby implicating their role in tumor-induced immunosuppression.
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