Adenosine Pathway of T Cell Regulation with a Chimeric Antigen Receptor

The development of CAR-T cells has become an important step in the treatment of hematological malignancies and solid tumors. However, the application of CAR-T cells is limited by the complex mechanisms of immunosuppression in the tumor microenvironment, including changes in the metabolic environment. Adenosine plays a key role in the functioning of the immune system, exerting an inhibitory effect on the immune response in the tumor microenvironment. It reduces the activity of T lymphocytes involved in antitumor immunity and inhibits phagocytosis, which allows the tumor to evade immune control. In tumor cells, adenosine stimulates epithelial-mesenchymal transition, inhibits apoptosis and promotes tumor cell proliferation. Various molecular genetic strategies are being developed to overcome the immunosuppressive effect of adenosine. Currently, clinical trials are underway aimed at suppressing the adenosine pathway using antibodies against CD39 and CD73, A2A receptor inhibitors, and overexpression of adenosine deaminase. In this review, we examine the latest advances in the regulation of the adenosine pathway in the regulation of CAR-T cell metabolism to improve the functioning of these cells in the treatment of various forms of cancer. At present, a promising strategy for increasing the effectiveness of CAR-T cells in the treatment of solid cancers is combined CAR-T cells with overexpression of the ADA enzyme and genetic suppression of adenosine pathway receptors and immunosuppressive factors (IL-10, FOXP3) using CRISPR/Cas9 or epigenetic editing.