Intercellular crosstalk shapes purinergic metabolism and signaling in cancer cells

CD73-derived adenosine suppresses anti-cancer immunity, and CD73 inhibitors are currently evaluated in several clinical trials. Here, we have assessed enzyme kinetics of all key purinergic ectoenzymes in five cancer cell lines (Hodgkin lymphoma, multiple myeloma, pancreas adenocarcinoma, urinary bladder carcinoma, and glioblastoma) under normoxia and hypoxia. We found that adenosine metabolism varied considerably between individual cancer types. All cell lines investigated exhibited high ecto-adenosine deaminase (ADA) activity, which critically influenced the kinetics of adenosine accumulation. Combining kinetics data with single-cell RNA sequencing data on myeloma and glioblastoma cancerous tissue revealed that purine metabolism is not homogeneously organized, but it differs in a cancer type-specific fashion between malignant cells, stromal cells, and immune cells. Since purine metabolism in cancerous tissue is most likely spatially heterogeneous and differs between the various cell types, diffusion distances in the microenvironment as well as ADA activity may be important variables that influence the level of bioactive adenosine. [Display omitted] •Extracellular adenosine metabolism varies considerably between cancer cell types•Ectoenzyme cascades generating adenosine are not linearly present on cancer cells•Adenosine production from ATP requires enzymes of surrounding non-cancer cells•ADA activity on cancer cells critically influences extracellular adenosine levels Hesse et al. compare the extracellular metabolism of anti-inflammatory adenosine used for immunoevasion in different cancer types. They show that the ectoenzyme cascade generating adenosine from nucleotides is not linearly present on cancer cells but requires enzyme activities of surrounding non-cancer cells for extracellular adenosine production.