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The brakes of inflammation

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February 26, 2013



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 tumor cells.

“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 petri dish.

“The killer cells 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 immune system’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 immunotherapy techniques.