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

Immunometabolic reprogramming due to adenosine produced by CD73 (encoded by the 5'-ectonucleotidase gene ) 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 human NK cells to directly target the CD73-adenosine axis by blocking the enzymatic activity of CD73.

Functional expression of CD73 on human natural killer cells.

The production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73 cancer cells, this upregulation is not universal, nor is it often substantial.

Differentiation of natural killer cells from induced pluripotent stem cells under defined, serum- and feeder-free conditions.

Background Aims: Traditionally, natural killer (NK) cells are sourced from the peripheral blood of donors-a laborious and highly donor-specific process. Processes for generating NK cells from induced pluripotent stem cells (iPSCs) have demonstrated that it is possible to successfully generate renewable alloreactive NK cells that are not only functional in vivo but can also be genetically engineered for enhanced function. However, poor standardization and cumbersome differentiation procedures suggest that further improvements in the control of the differentiation process are necessary.

Immunometabolic Dysfunction of Natural Killer Cells Mediated by the Hypoxia-CD73 Axis in Solid Tumors.

NK cell infiltration into solid tumors is often low and is largely represented by the poorly-cytotoxic CD56 subset. Numerous studies have demonstrated that CD73, overexpressed under conditions of hypoxia, is involved in a variety of physiological processes, while its overexpression has been correlated with tumor invasiveness, metastasis and poorer patient survival in many cancers. Hypoxia itself favors aggressive glycolytic fueling of cancer cells, in turn driving reprogramming of NK cell metabolism.

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

Background: The anti-tumor immunity of natural killer (NK) cells can be paralyzed by the CD73-induced generation of immunosuppressive adenosine from precursor ATP within the hypoxic microenvironment of solid tumors. In an effort to redirect purinergic immunosuppression of NK cell anti-tumor function, we showed, for the first time, that immunometabolic combination treatment with NKG2D-engineered CAR-NK cells alongside blockade of CD73 ectonucleotidase activity can result in significant anti-tumor responses in vivo.

Methods: NK cells were engineered non-virally with NKG2D.

Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells.

Energy metabolism is key to the promotion of tumor growth, development, and metastasis. At the same time, cellular metabolism also mediates immune cell survival, proliferation and cytotoxic responses within the tumor microenvironment. The ability of natural killer cells to eradicate tumors relies on their ability to functionally persist for the duration of their anti-tumor effector activity.

Adenosinergic Signaling Alters Natural Killer Cell Functional Responses.

Adenosine is a potent immunosuppressive purine metabolite contributing to the pathogenesis of solid tumors. Extracellular adenosine signals on tumor-infiltrating NK cells to inhibit their proliferation, maturation, and cytotoxic function. Cytokine priming imparts upon NK cells distinct activation statuses, which modulate NK anti-tumor immunity and responses to purinergic metabolism.

Development of a Glycosaminoglycan Derived, Selectin Targeting Anti-Adhesive Coating to Treat Endothelial Cell Dysfunction.

Endothelial cell (EC) dysfunction is associated with many disease states including deep vein thrombosis (DVT), chronic kidney disease, sepsis and diabetes. Loss of the glycocalyx, a thin glycosaminoglycan (GAG)-rich layer on the EC surface, is a key feature of endothelial dysfunction and increases exposure of EC adhesion molecules such as selectins, which are involved in platelet binding to ECs. Once bound, platelets cause thrombus formation and an increased inflammatory response.