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Abstract Solid tumors are protected from antitumor immune responses due to their hypoxic microenvironments. Weakening hypoxia‐driven immunosuppression by hyperoxic breathing of 60% oxygen has shown to be effective in unleashing antitumor immune cells against solid tumors. However, efficacy of systemic oxygenation is limited against solid tumors outside of lungs and has been associated with unwanted side effects. As a result, it is essential to develop targeted oxygenation alternatives to weaken tumor hypoxia as novel approaches to restore immune responses against cancer. Herein, injectable oxygen‐generating cryogels (O2‐cryogels) to reverse tumor‐induced hypoxia are reported. These macroporous biomaterials are designed to locally deliver oxygen, inhibit the expression of hypoxia‐inducible genes in hypoxic melanoma cells, and reduce the accumulation of immunosuppressive extracellular adenosine. The data show that O2‐cryogels enhance T cell‐mediated secretion of cytotoxic proteins, restoring the killing ability of tumor‐specific cytotoxic T lymphocytes, both in vitro and in vivo. In summary, O2‐cryogels provide a unique and safe platform to supply oxygen as a coadjuvant in hypoxic tumors and have the potential to improve cancer immunotherapies.
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Controlling Pericellular Oxygen Tension in Cell Culture Reveals Distinct Breast Cancer Responses to Low Oxygen Tensions
Abstract In oxygen (O2)‐controlled cell culture, an indispensable tool in biological research, it is presumed that the incubator setpoint equals the O2tension experienced by cells (i.e., pericellular O2). However, it is discovered that physioxic (5% O2) and hypoxic (1% O2) setpoints regularly induce anoxic (0% O2) pericellular tensions in both adherent and suspension cell cultures. Electron transport chain inhibition ablates this effect, indicating that cellular O2consumption is the driving factor. RNA‐seq analysis revealed that primary human hepatocytes cultured in physioxia experience ischemia‐reperfusion injury due to cellular O2consumption. A reaction‐diffusion model is developed to predict pericellular O2tension a priori, demonstrating that the effect of cellular O2consumption has the greatest impact in smaller volume culture vessels. By controlling pericellular O2tension in cell culture, it is found that hypoxia vs. anoxia induce distinct breast cancer transcriptomic and translational responses, including modulation of the hypoxia‐inducible factor (HIF) pathway and metabolic reprogramming. Collectively, these findings indicate that breast cancer cells respond non‐monotonically to low O2, suggesting that anoxic cell culture is not suitable for modeling hypoxia. Furthermore, it is shown that controlling atmospheric O2tension in cell culture incubators is insufficient to regulate O2in cell culture, thus introducing the concept of pericellular O2‐controlled cell culture.
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- Award ID(s):
- 1847843
- PAR ID:
- 10532959
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Science
- Volume:
- 11
- Issue:
- 30
- ISSN:
- 2198-3844
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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