Scientists at Northeastern University have discovered that supplemental oxygenation can shrink tumors and may improve cancer immunotherapy. The findings (“Immunological mechanisms of the antitumor effects of supplemental oxygenation”) were published in Science Translational Medicine.

Working with mouse models, Michail Sitkovsky, Ph.D., and his team found that supplemental oxygenation inhibits the hypoxia-driven accumulation of adenosine in the tumor microenvironment and weakens immunosuppression. This, in turn, could improve cancer immunotherapy and shrink tumors by unleashing antitumor T lymphocytes and natural killer cells.

“This discovery shifts the paradigm of decades-long drug development, a process with a low success rate,” said Dr. Sitkovsky, the Eleanor W. Black Chair and professor of immunophysiology and pharmaceutical biotechnology and the founding director of the university's New England Inflammation and Tissue Protection Institute. “Indeed, it is promising that our method could be implemented relatively quickly by testing in clinical trials the effects of oxygenation in combination with different types of already existing immunotherapies of cancer.”

In the early 2000s, Dr. Sitkovsky made a discovery in immunology, which he says has greatly informed his research in cancer biology. He found that a receptor on the surface of immune cells (the A2A adenosine receptor) is responsible for preventing T cells from invading tumors and for “putting to sleep” those killer cells that do manage to enter into the tumors.

His latest work shows that inhaling 40–60% oxygen (air offers 21% oxygen) weakened tumor-protecting signaling through the A2A adenosine receptor and awakened T cells that had gained the ability to invade lung tumors.

“Respiratory hyperoxia also promoted the regression of spontaneous metastasis from orthotopically grown breast tumors,” wrote the investigators.” These effects are entirely T cell—and natural killer cell—dependent, thereby justifying the testing of supplemental oxygen as an immunological coadjuvant to combine with existing immunotherapies for cancer.”

“Breathing supplemental oxygen opens up the gates of the tumor fortress and wakes up 'sleepy' antitumor cells, enabling these soldiers to enter the fortress and destroy it,” Dr. Sitkovsy explained. “However,” he added, “if antitumor immune cells are not present, oxygen will have no impact.”

He further noted that the effects of supplemental oxygenation might be even stronger in combination with a synthetic agent that he calls “super-caffeine,” which is known to block the tumor-protecting effects of the adenosine receptor. He and Graham Jones, Ph.D., professor and chair of Northeastern's department of chemistry and chemical biology, are currently collaborating to design the next generation of this drug, which was originally developed for patients with Parkinson's disease.

“The antitumor effects of supplemental oxygen can be further improved by the natural antagonist of the A2A adenosine receptor, which happens to be the caffeine in your coffee,” Dr. Sitkovsky said. “People drink coffee because caffeine prevents the A2A adenosine receptor in the brain from putting us to sleep.” 

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