Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors

Abstract

Immunometabolic reprogramming due to CD73-produced adenosine is a recognized immunosuppressive mechanism contributing to immune evasion in solid tumors. Adenosine is not only known to contribute to tumor progression, but it has specific roles in driving dysfunction of immune cells, including natural killer (NK) cells. Here, we engineered NK cells to directly target the CD73-adenosine axis by blocking the enzymatic activity of CD73. In doing so, the engineered NK cells not only impaired adenosinergic metabolism driven by the hypoxic uptake of ATP by cancer cells, but also mediated killing of tumor cells due to the specific recognition of overexpressed CD73. This results in a "single agent" immunotherapy that combines antibody specificity, blockade of purinergic signaling, and killing of targets mediated by NK cells. We also showed that CD73-targeted NK cells are potent in vivo and result in tumor arrest, while promoting NK cell infiltration into CD73+ tumors and enhanced intratumoral activation.

Unveiling the Immunological Terrain of Pancreatic Ductal Adenocarcinoma: Strategies to Prompt Immunotherapy from Mendelian Randomization

“…For instance, lactate, a byproduct of aerobic glycolysis, creates an acidic TME that inhibits T cell activity and promotes the polarization of M2 macrophages [41]. Similarly, adenosine accumulation has been shown to impair NK cell function and promote Treg activity [42]. Emerging research highlights the signi cant impact of the gut microbiota on systemic immunity and cancer.…”