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Scheme 1 | Journal for ImmunoTherapy of Cancer

Scheme 1

From: Purinergic targeting enhances immunotherapy of CD73+ solid tumors with piggyBac-engineered chimeric antigen receptor natural killer cells

Scheme 1

CD73-mediated adenosinergic cascade and CAR-NK immunotherapy. a Extracellular adenosine (ADO) metabolism in the tumor microenvironment and its inhibition of NK cell effector functions. Two ectoenzymes, E-NTPDase1 (CD39) and ecto-5’-Nucleotidase (CD73), which are highly overexpressed on many solid tumors, convert extracellular ATP to ADP/AMP and AMP to ADO, respectively, leading to elevated levels of ADO in the tumor microenvironment. ADO signals on adenosine receptors on NK cells, ultimately suppressing their immune response. The release of ADO is modulated by adenosine deaminase (ADA), which deaminates ADO to inosine. b Combination immunotherapy with NKG2D.CAR-NK cells and anti-CD73 antibody enhances suppression of tumor growth. NKG2D.CAR-NK cells are engineered with a synthetic immunoreceptor which recognizes MHC class I-like ligand MICA, resulting in an increase in their antitumor capacity through antigen-receptor binding, by counteracting TME-induced downregulation of NKG2D. Co-administration of anti-CD73 antibody can modulate tumor metabolism by redirecting purinergic signaling through blockade of ADO production

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