High expression of CD39 in gastric cancer reduces patient outcome following radical resection

Abstract

Abstract. Ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1), also known as cluster of differentiation (CD)39, is the rate-limiting enzyme in the generation of immunosuppressive adenosine and is important in tumor progression. The present study evaluated the expression of CD39 + and CD39 + forkhead box P3 (FoxP3) + regulatory T (Treg) cells in gastric cancer (GC), and determined their prognostic roles in patients with GC following radical resection. It was observed that CD39 was expressed at significantly higher rates in tumor tissues as compared with paired peritumoral tissues. Overexpression of tumor CD39 was correlated with overall survival (OS). Furthermore, CD39 expression in GC tissues exhibited a prognostic role in OS. The CD39 + FoxP3 + /FoxP3 + ratio in tumor tissues was higher than that in paired peritumoral tissues, and CD39 + FoxP3 + Treg cells were a better prognostic indicator than FoxP3 + Treg cells for OS. Collectively, our study indicates that overexpression of CD39 in GC is a predictor of poor outcome for GC patients following radical resection. CD39 + FoxP3 + Treg cells are a potential target for cancer immunotherapy.

Multifaceted Effects of Extracellular Adenosine Triphosphate and Adenosine in the Tumor–Host Interaction and Therapeutic Perspectives

“…Increased expression of CD39 has been widely reported in several tumors, such as medulloblastoma ( 214 ), sarcoma ( 215 ), HCC ( 216 ), pancreatic cancer ( 217 ), colorectal cancer ( 218 , 219 ), gastric cancer ( 216 ), and endometrial cancer ( 220 ); as well as in infiltrating immune cells ( 216 , 221 – 224 ) and tumor endothelial cells ( 216 , 225 ), influencing tumor growth, metastasis and angiogenesis. As an example, expression of CD39 by Tregs plays a permissive role in a mouse model of hepatic metastasis by inhibiting NK cell antitumor immunity and contributing to tumor immune escape ( 226 ).…”

Targeting adenosine for cancer immunotherapy

“…Furthermore, predicts better outcome in the subgroup of pTa and pT1 tumors. 174 Wettstein, et al [ 61 ] Breast Cancer (stage I-III) CD73 expression strongly correlated with longer disease-free survival and overall survival 136 Supernat, et al [ 62 ] Endometrial Carcinoma (endometrial endometrioid carcinomas, Grade 1–3) and nonendometrioid uterine papillary serous carcinomas CD73 is markedly downregulated in poorly differentiated and advanced-stage disease compared with levels in normal endometrium and low-grade tumors 49 Bowser, et al [ 64 ] Colorectal cancer (Stage IV) High CD73 expression was associated with longer progression free survival from cetuximab treatment in patients with KRAS-WT and KRAS-mutant tumors 238 Cushman, et al [ 63 ] CD39 Negatively prognostic Gastric Cancer (stage I-IV) High CD39 expression is a predictor of poor outcome following radical resection 101 Cai, et al [ 69 ] Hepatocellular carcinoma High CD39 expression is an independent indicator of decreased overall suvival after radical resection 324 Cai, et al [ 70 ] Chronic lymphocytic leukemia CD39 expression on CD4+ lymphocytes are increased in the peripheral blood of patients with CLL and correlates with advanced stage of disease 62 Perry, et al [ 71 ] …”

Progress in the treatment of advanced gastric cancer

“…53 The immune system can be used to identify and clear malignant tumors via immune surveillance to inhibit tumor development. 54 Inhibiting T-cell activity via the inhibitory signaling pathways involved with immunological detection points is an important mechanism by which tumor cells evade hostmediated immune recognition and killing. Therefore, immunoregulatory antibodies that target immune cell surface antigens block immunosuppressive signals and enhance immune cell activity representing a new direction in tumor therapy.…”