Entpd1, also known as CD39, is an ectonucleotidase that plays a strategic role in the purinergic signaling pathway. It is the rate-limiting enzyme in the cascade converting ADP/ATP to AMP, which can ultimately lead to the generation of immunosuppressive adenosine through the action of CD73 [1,2,3]. This pathway is crucial in calibrating the immune response, shifting from a pro-inflammatory ATP-driven environment to an anti-inflammatory adenosine-induced milieu, and thus is important in various pathophysiological events [2]. Gene knockout models have been instrumental in studying its function.

In cancer, knockout models have shown that Entpd1 plays a significant role. In hepatic metastatic cancer models, Cd39 null mice or wild-type mice with circulating Cd39 null bone marrow-derived cells had strongly inhibited hepatic growth of melanoma metastatic tumors, indicating that CD39 expression on CD4+Foxp3+ regulatory T cells (Tregs) promotes tumor growth by suppressing antitumor immunity mediated by natural killer cells [6]. In colorectal cancer, disrupting the Entpd1 gene in engineered T cells targeting HER-2 conferred a functional advantage in eliminating HER-2+ patient-derived organoids in vitro and in vivo, highlighting CD39 as a major driver of T-cell exhaustion [5]. In addition, in a sepsis model, CD39-/-mice exhibited higher levels of inflammatory cytokines and more pronounced liver injury than wild-type mice, suggesting that CD39 attenuates sepsis-associated liver injury by scavenging extracellular ATP [4].

In conclusion, Entpd1 is a key enzyme in the purinergic signaling pathway, playing a crucial role in immune regulation. Gene knockout mouse models have revealed its significance in cancer, such as promoting metastatic tumor growth and being a driver of T-cell exhaustion, as well as in sepsis-induced liver injury. Understanding Entpd1 function through these models provides potential therapeutic targets for these diseases.

References:

1. Bastid, J, Cottalorda-Regairaz, A, Alberici, G, Eliaou, J-F, Bensussan, A. 2012. ENTPD1/CD39 is a promising therapeutic target in oncology. In Oncogene, 32, 1743-51. doi:10.1038/onc.2012.269. https://pubmed.ncbi.nlm.nih.gov/22751118/

2. Antonioli, Luca, Pacher, Pál, Vizi, E Sylvester, Haskó, György. 2013. CD39 and CD73 in immunity and inflammation. In Trends in molecular medicine, 19, 355-67. doi:10.1016/j.molmed.2013.03.005. https://pubmed.ncbi.nlm.nih.gov/23601906/

3. Timperi, Eleonora, Barnaba, Vincenzo. 2021. CD39 Regulation and Functions in T Cells. In International journal of molecular sciences, 22, . doi:10.3390/ijms22158068. https://pubmed.ncbi.nlm.nih.gov/34360833/

4. Savio, Luiz Eduardo Baggio, de Andrade Mello, Paola, Figliuolo, Vanessa R, Robson, Simon C, Coutinho-Silva, Robson. 2017. CD39 limits P2X7 receptor inflammatory signaling and attenuates sepsis-induced liver injury. In Journal of hepatology, 67, 716-726. doi:10.1016/j.jhep.2017.05.021. https://pubmed.ncbi.nlm.nih.gov/28554875/

5. Potenza, Alessia, Balestrieri, Chiara, Spiga, Martina, Ruggiero, Eliana, Bonini, Chiara. 2023. Revealing and harnessing CD39 for the treatment of colorectal cancer and liver metastases by engineered T cells. In Gut, 72, 1887-1903. doi:10.1136/gutjnl-2022-328042. https://pubmed.ncbi.nlm.nih.gov/37399271/

6. Sun, Xiaofeng, Wu, Yan, Gao, Wenda, Murakami, Takashi, Robson, Simon C. 2010. CD39/ENTPD1 expression by CD4+Foxp3+ regulatory T cells promotes hepatic metastatic tumor growth in mice. In Gastroenterology, 139, 1030-40. doi:10.1053/j.gastro.2010.05.007. https://pubmed.ncbi.nlm.nih.gov/20546740/