作者: Cowell, Jessica ; Shepard, H. Michael ; Cekic, Caglar ; Thanos, Christopher D. ; Ersan, Pelin G. ; Zhao, Qiping ; Aras, Mertkaya ; LaBarre, Michael J. ; Pei, Hong ; Londono, Luz M. ; Huang, Lei ; Saatci, Ozge ; Sahin, Ozgur ; Deaglio, Silvia ; Wang, Lin ; Linden, Joel ; Li, Xiaoming ; Clift, Renee ; Serra, Sara ; Phan, Kim B.

AbstractExtracellular adenosine in tumors can suppress immune responses and promote tumor growth. Adenosine deaminase 2 (ADA2) converts adenosine into inosine. The role of ADA2 in cancer and whether it can target adenosine for cancer therapy has not been investigated. Here we show that increased ADA2 expression is associated with increased patient survival and enrichment of adaptive immune response pathways in several solid tumor types. Several ADA2 variants were created to improve catalytic efficiency, and PEGylation was used to prolong systemic exposure. In mice, PEGylated ADA2 (PEGADA2) inhibited tumor growth by targeting adenosine in an enzyme activity–dependent manner and thereby modulating immune responses. These findings introduce endogenous ADA2 expression as a prognostic factor and PEGADA2 as a novel immunotherapy for cancer.Significance:This study identifies ADA2 as a prognostic factor associated with prolonged cancer patient survival and introduces the potential of enzymatic removal of adenosine with engineered ADA2 for cancer immunotherapy.

2016-05-15·Cancer Research1区 · 医学

Extracellular Adenosine Production by ecto-5′-Nucleotidase (CD73) Enhances Radiation-Induced Lung Fibrosis

1区 · 医学

Article

作者: Fischer, Ute ; Stuschke, Martin ; Ritchey, Jerry W. ; Cappuccini, Federica ; Wirsdörfer, Florian ; Blackburn, Michael R. ; Klein, Diana ; Gau, Eva ; Thompson, Linda F. ; Meyer, Alina V. ; de Leve, Simone ; Westendorf, Astrid M. ; Karmouty-Quintana, Harry ; Jendrossek, Verena ; Kasper, Michael ; Chen, Ning-Yuan ; Eldh, Therese

AbstractRadiation-induced pulmonary fibrosis is a severe side effect of thoracic irradiation, but its pathogenesis remains poorly understood and no effective treatment is available. In this study, we investigated the role of the extracellular adenosine as generated by the ecto-5′-nucleotidase CD73 in fibrosis development after thoracic irradiation. Exposure of wild-type C57BL/6 mice to a single dose (15 Gray) of whole thorax irradiation triggered a progressive increase in CD73 activity in the lung between 3 and 30 weeks postirradiation. In parallel, adenosine levels in bronchoalveolar lavage fluid (BALF) were increased by approximately 3-fold. Histologic evidence of lung fibrosis was observed by 25 weeks after irradiation. Conversely, CD73-deficient mice failed to accumulate adenosine in BALF and exhibited significantly less radiation-induced lung fibrosis (P < 0.010). Furthermore, treatment of wild-type mice with pegylated adenosine deaminase or CD73 antibodies also significantly reduced radiation-induced lung fibrosis. Taken together, our findings demonstrate that CD73 potentiates radiation-induced lung fibrosis, suggesting that existing pharmacologic strategies for modulating adenosine may be effective in limiting lung toxicities associated with the treatment of thoracic malignancies. Cancer Res; 76(10); 3045–56. ©2016 AACR.

2013-06-01·The FASEB Journal2区 · 生物学

CD73 ⁺ regulatory T cells contribute to adenosine‐mediated resolution of acute lung injury

2区 · 生物学

Article

作者: Riegel, Ann K. ; Colgan, Sean P. ; Poth, Jens M. ; Brodsky, Kelley S. ; Clambey, Eric T. ; Westrich, Joseph A. ; McNamee, Eoin N. ; Eltzschig, Holger K. ; Ehrentraut, Stefan F. ; Ehrentraut, Heidi

Acute lung injury (ALI) is characterized by alveolar injury and uncontrolled inflammation. Since most cases of ALI resolve spontaneously, understanding the endogenous mechanisms that promote ALI resolution is important to developing effective therapies. Previous studies have implicated extracellular adenosine signaling in tissue adaptation and wound healing. Therefore, we hypothesized a functional contribution for the endogenous production of adenosine during ALI resolution. As a model, we administered intratracheal LPS and observed peak lung injury at 3 d, with resolution by d 14. Treatment with pegylated adenosine-deaminase to enhance extracellular adenosine breakdown revealed impaired ALI resolution. Similarly, genetic deletion of cd73, the pacemaker for extracellular adenosine generation, was associated with increased mortality (0% wild-type and 40% in cd73(-/-) mice; P<0.05) and failure to resolve ALI adequately. Studies of inflammatory cell trafficking into the lungs during ALI resolution revealed that regulatory T cells (Tregs) express the highest levels of CD73. While Treg numbers in cd73(-/-) mice were similar to controls, cd73-deficient Tregs had attenuated immunosuppressive functions. Moreover, adoptive transfer of cd73-deficient Tregs into Rag(-/-) mice emulated the observed phenotype in cd73(-/-) mice, while transfer of wild-type Tregs was associated with normal ALI resolution. Together, these studies implicate CD73-dependent adenosine generation in Tregs in promoting ALI resolution.

100 项与 PEG-ADA2 相关的药物交易

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