Rare Immune Cell Is Key To Transplant's Cancer-killing Effect

Scientists call it the graft-versus-leukemia effect, and it occurs whennew immune cells from donated bone marrow, called the graft, attackmalignant cells in the patient and destroy them. This intense immunereaction between donor and host cells, which follows a bone marrowtransplant from a healthy donor, has saved the lives of thousands ofpatients with leukemia, lymphoma and other types of blood and immunesystem cancers.

In a study to be published Oct. 16 in the advanced onlineedition of Nature Medicine, U-M scientists describe how antigenpresenting cells are crucial to graft-versus-leukemia's cancer-killingeffect.

The discovery is significant, because it could help make cellularimmunotherapy safer, more effective and an option for more cancerpatients -- especially those for whom a donor is unavailable or thosewho cannot tolerate the procedure's side-effects.

"We already knew that donor T cells were important for aneffective GVL response, but now we know there's another cell -- theantigen presenting cell or APC -- which plays a critical role in theprocess," says James L.M. Ferrara, M.D., who directs the U-M CancerCenter's Blood and Marrow Transplant Program.

Antigen presenting cells are rare immune system cells, which looksomething like a starfish. Their job is to digest proteins calledantigens from foreign cells or pathogens and present them to T cells.This alerts the immune system to prepare to fight the invader. WhenAPCs present cancer cell proteins to T cells, the T cells are primed toattack the cancer.

"We found that without functional APCs to process and presentantigens to T cells, there is no graft-versus-leukemia response, andthe cancer is likely to return," says Pavan R. Reddy, M.D., anassistant professor of internal medicine in the University of MichiganMedical School, who led the research study.

According to Reddy, the research results suggest that manipulating thenumber and activity of APCs could improve the GVL response, whilereducing the risk of a common post-transplant complication calledgraft-versus-host disease, or GVHD.

"GVHD occurs when the donor's immune cells attack thepatient's skin, liver and gastrointestinal tract," Reddy explains. "Ittriggers a massive inflammatory reaction that can kill the patient,especially if he or she is older or has other medical problems."

In an effort to eliminate GVHD, other researchers havesuggested removing APCs from transplanted donor cells, according toFerrara. "We know that APCs are involved in graft-versus-host disease,so people say let's take out the APCs and then we will get theanti-cancer effect without the risk of GVHD," he explains. "This papersays, no, you can't do that.

"There's a tight link between the graft-versus-leukemia effectand graft-versus-host disease," Ferrara says. "Few patients get thebeneficial effects of GVL without some degree of the toxic side effectsof GVHD. But if we can find ways to reduce GVHD's toxic effects,immunotherapy could become a viable option for many more cancerpatients."

To study what happens during the graft-versus-leukemia effect,Reddy and his U-M colleagues used high doses of radiation to destroythe blood and immune systems of genetically different laboratory mice.After reconstituting each animal's immune system, using eitherfunctional or non-functional APCs, the mice were inoculated with cancercells and given a bone marrow transplant that could cure the cancer.The scientists then determined which mice died from acutegraft-versus-host disease, which mice died from cancer and which micegenerated a GVL response to destroy the cancer cells.

"The donor and host mice were paired in ways to make theirantigen-presenting cells dysfunctional, either because they were of thesame tissue type as the donor, or because they had a mutation thatprevented them from displaying tumor antigens to T cells," Reddyexplains. "Essentially we created animals where the tumor was the same,the antigens were the same, donor T cells were the same, but the APCwas dysfunctional. Without a functioning APC, there was nograft-versus-leukemia effect."

Other researchers have suggested that tumor cells can presentantigens to T cells directly to stimulate an immune response againstcancer, but results from the U-M study indicate the response is tooweak to be effective.

"APCs shred proteins, or antigens, from cancer cells anddisplay those shredded proteins on their surface," Ferrara says."Cancer cells have the same proteins, but haven't gone through theAPC's shredding process. It's as if APCs are master chefs who preparethe antigens in a way to make them especially delicious to T cells. Soinstead of taking just one bite, they go back for seconds or thirds."

In future research, U-M scientists will explore how tomanipulate APC function in ways that will preserve their vital role instimulating an immune response against cancer, while controlling theintensity of graft-versus-host disease. Reddy and Ferrara have studieddrugs called HDAC inhibitors and found that they modulate APC functionin mice. They hope to design an initial study of these drugs inpost-transplant leukemia patients within a year.

The research was funded by the National Cancer Institute.Collaborators included Yoshinobu Maeda, M.D., a former U-M researchfellow; Oleg I. Krijanovski, M.D., a research fellow in internalmedicine; Chen Liu, M.D., a pathologist at the University of FloridaCollege of Medicine; and Robert Korngold, M.D., Ph.D., an immunologistand scientific director of the Hackensack University Cancer Center.