Northeastern researchers find inhaling supplemental oxygen can awaken anti-tumor cells

Northeastern University researchers have found that inhaling supplemental oxygen—40 to 60 percent oxygen as opposed to the 21 percent oxygen in air—can weaken immunosuppression and awaken anti-tumor cells. The new approach, some 30 years in the making, could dramatically increase the survival rate of patients with cancer, which kills some 8 million people each year. The breakthrough findings were published Wednesday in Science Translational Medicine.

Michail Sitkovsky, an immuno­phys­i­ology researcher at North­eastern Uni­ver­sity, 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 anti-​​tumor T lym­pho­cytes and nat­ural killer cells.

“Breathing sup­ple­mental oxygen opens up the gates of the tumor fortress and wakes up ‘sleepy’ anti-​​tumor cells, enabling these sol­diers to enter the fortress and destroy it,” explained Sitkovsky, the Eleanor W. Black Chair and Pro­fessor of Immuno­phys­i­ology and Phar­ma­ceu­tical Biotech­nology in the Bouvé College of Health Sciences’ Department of Pharmaceutical Sciences and the founding director of the university’s New Eng­land Inflam­ma­tion and Tissue Pro­tec­tion Insti­tute. “How­ever, if anti-​​tumor immune cells are not present, oxygen will have no impact.”

The find­ings build upon Sitkovsky’s pre­vious research and rep­re­sent the cul­mi­na­tion of his life’s work, which has been sup­ported by North­eastern and the National Insti­tutes of Health. In the early 2000s, Sitkovsky made an impor­tant dis­covery in immunology, which has come to inform 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 supplemental oxygen weakened tumor-​​protecting sig­naling through the A2A adeno­sine receptor and wakes up the T cells that were able to invade lung tumors.“This dis­covery shifts the par­a­digm of decades-​​long drug devel­op­ment, a process with a low suc­cess rate,” Sitkovsy said. “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.”

Sitkovsky 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, 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 anti-​​tumor 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,” Sitkovsky said. “People drink coffee because caf­feine pre­vents the A2A adeno­sine receptor in the brain from putting us to sleep.”

The paper—titled “Immuno­log­ical mech­a­nisms of the anti­tumor effects of sup­ple­mental oxygenation”—was the result of a robust inter­dis­ci­pli­nary col­lab­o­ra­tion between doc­tors and researchers at some of the country’s most pres­ti­gious uni­ver­si­ties, hos­pi­tals, and med­ical schools. Co-​​authors com­prised 12 researchers from NEITPI, the Northeastern-​​based con­sor­tium aimed at under­standing the under­lying causes and mol­e­c­ular mech­a­nisms of inflam­ma­tion; Barry Karger, the director of Northeastern’s Bar­nett Insti­tute of Chem­ical and Bio­log­ical Analysis; and doc­tors from the Uni­ver­sity of Pitts­burgh School of Med­i­cine, the Uni­ver­sity of Miami Miller School of Med­i­cine, Brigham and Women’s Hos­pital, and the Dana-​​Farber Cancer Insti­tute, where Sitkovsy holds an appoint­ment as a pres­i­den­tial scholar.