The brakes of inflammation

by Angela Herring
Professor Michail Sitkovsky’s work on adenosine receptors has spurred a body of research recently reviewed in the New England Journal of Medicine. Credit: Brooks Canaday

In the last few decades, sci­en­tists have come to attribute an immuno­log­ical expla­na­tion to many can­cers. It is now thought that tumors rise up rou­tinely in the body but that a healthy immune system blocks their devel­op­ment. Thus, for patients who do develop cancer, the immune system is par­tially to blame.

Treat­ment has there­fore come to involve immunotherapy, in which clin­i­cians stim­u­late a patient's immune system with cancer vac­cines. The immune system responds by cre­ating T-​​cells whose job is to kill the .

"But immunotherapy of cancer doesn't live up to expec­ta­tions," according to North­eastern pro­fessor Michail Sitkovsky, adding that T-​​cells induced by cancer vac­cines simply don't kill tumor cellss inside the body, though they do so quite well in a .

"The were alert and eager to kill the tumor, but the tumor man­aged to put the killer to sleep," said Sitkovsky, the Eleanor W. Black Chair and Pro­fessor of Immuno­phys­i­ology and Phar­ma­ceu­tical Biotech­nology and founding director of Northeastern's New Eng­land Inflam­ma­tion and Tissue Pro­tec­tion Insti­tute. "This is what hap­pens in a majority of cancers."

But what, Sitkovsky wanted to know, puts the killer cells to sleep?

His desire to find out spurred him and his research team to dis­cover a sig­naling pathway that he calls "the brakes of the immune system," which was reported in 2001 in the journal Nature. In the last sev­eral years, many researchers have fol­lowed up on Sitkovsky's work, impli­cating the pathway in a variety of inflam­ma­tory dis­eases. In a recent article in the esteemed New Eng­land Journal of Med­i­cine, he and his col­leagues at the Uni­ver­sity of Col­orado School of Med­i­cine and Har­vard Med­ical School reviewed the body of work that has emerged since Sitkovsky's discovery.

The find­ings indi­cated that, during inflam­ma­tion, mol­e­cules called "purines" are released from cells and act as phys­i­o­log­ical brake pedals by inhibiting an immune response. "This is how the immune system works," said Sitkovsky. "It is acti­vated to kill pathogens, but it also has brakes because the immune system does a lot of col­lat­eral damage to inno­cent bystanders."

The most impor­tant among these bystanders are the cells lining our blood ves­sels. "Because of damage to blood ves­sels, there is inter­rup­tion of blood supply," Sitkovsky explained. "No blood supply: no oxygen supply." This lack of oxygen is called hypoxia, which trig­gers the release of a purine mol­e­cule called adeno­sine. When adeno­sine binds to recep­tors on the sur­face of T-​​cells, they stop their killing spree, acting as the 's brake pedal.

And here's the clincher: Tumors, which grow so quickly that blood ves­sels can't keep up with them, have evolved to per­se­vere in the absence of oxygen and are inher­ently hypoxic. As a result, they are rid­dled with adenosine.

"So killers come"—here Sitkovsky grasped his throat and pre­tended to asphyxiate—"and then run away!"

To forcibly restore T-​​cells' immuno­log­ical func­tion, he and his team of researchers looked for a drug that would block the effects of adeno­sine. In a great stroke of luck, it turned out that the most widely used and easily accessed psy­choac­tive drug in the world—caffeine—does just that.

Sitkovsky looked to epi­demi­ology for evi­dence of a cor­re­la­tion between coffee drinkers and tumor sup­pres­sion and found that dozens of studies with hun­dreds of thou­sands of par­tic­i­pants showed that coffee seemed to have a cancer-​​preventive effect in women. The pat­tern wasn't as strong among males, because testos­terone, like adeno­sine, is another immunosuppressant.

The team's pre­clin­ical studies using high doses of caf­feine to block adeno­sine resulted in tumor rejec­tion and mouse sur­vival. The results were reported in the Pro­ceed­ings of the National Academy of Sci­ences in 2006 and the approach is now being tested in human clin­ical trials in con­junc­tion with tra­di­tional cancer techniques.

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Anthony1888
not rated yet Feb 27, 2013
this is true. everyone has cancer. my mother just recently got cancer and instead of radiation she went to a homiopathic doctor and boosted her immune system of what it needed and shes cured. this is old news. maybe now it will be popular because of this "new discovery..."
tekram
not rated yet Feb 27, 2013
Holger K. Eltzschig, Michail V. Sitkovsky, Simon C. Robson. Purinergic Signaling during Inflammation. New England Journal of Medicine, 2012; 367 (24): 2322 DOI: 10.1056/NEJMra1205750