Echoes of past encounters with leukemia flow through the veins of people who have never suffered from the disease, a study suggests. The immune systems of cancer-free people may have gathered antileukemia forces by mounting preemptive strikes against cells that were on their way to becoming cancerous. Leukemia patients, on the other hand, carry meager signs of resistance.
“Perhaps we’ve all had a bit of precancerous disease,” says immunologist Mark Cobbold of the University of Birmingham in England, who led the study with Birmingham colleague Hugo De La Peña. Just as immune cells reflect a person’s history of viral infections, the fingerprint of cancer exposures could lie there as well, Cobbold says.
After an encounter with any pathogen, a fraction of immune cells that fought in the battle stick around, lying in wait for the next attack. Cobbold, De La Peña and their colleagues found in healthy people killer immune cells that appeared to have been scent-trained on cancer cells. And the scientists identified the scent as well: a family of peptides, or small fragments of proteins, that coat the surfaces of cancer cells.
The peptides come from proteins inside the cell — signposts that killer cells called T cells normally use to sniff out virus-infected cells. The cancer peptides were adorned with chemical modifications called phosphate groups. The addition of phosphate groups to proteins communicates signals that control cell growth and survival. But cancer cells switch this process into overdrive, says De La Peña. “The cancer cell needs this ‘crazy phosphorylation’ to become malignant,” he says. “And this is exactly what the immune system sees.”
The team identified 95 of these phosphopeptides on the surfaces of malignant cells taken from patients with leukemia. Sixty-one of the peptides appeared only on cancer cells and not on normal ones, the researchers report in the Sept. 18 Science Translational Medicine.
Then the team extracted T cells from 26 leukemia patients: 14 with chronic lymphocytic leukemia and 12 with acute myeloid leukemia, a more aggressive form of the disease. While healthy volunteers all harbored T cells that recognized the cancer phosphopeptides, only five patients with the milder leukemia did, as did two patients with acute myeloid leukemia. The researchers found that the T cells bore proteins that marked them as “memory cells,” indicating that the cells had encountered the phosphopeptides — perhaps on cancerous cells — before.
The reasons some people lack this immunity to the phosphopeptides are unclear, but the researchers speculate that those people may have had the cancer-specific killer cells and then lost them as the immune system waned with age. Or perhaps some people’s immune cells never mounted a response in the first place.
After researchers measured T cells from the patients, the 12 individuals with acute myeloid leukemia received stem cell transplants to treat their disease. Ten of them then showed immune responses to some of the peptides.
If other experiments confirm that donated cells can prime a person’s immune system to respond to phosphopeptides, Cobbold proposes that screening donors for immunity to phosphopeptides could improve the success of transplants as treatment.
The researchers hope to find phosphopeptide signatures on other kinds of cancer as well and envision using the peptides to vaccinate people against cancer.
“It’s a sort of tantalizing result,” says immunologist Anthony Purcell of Monash University in Melbourne, Australia. Cancer phosphopeptides, he says, likely won’t be a “global panacea.” But he calls them exciting and “a new part of the cancer vaccination toolkit.”
M. Cobbold et al. MHC Class I-associated phosphopeptides are the targets of memory-like immunity to leukemia. Science Translational Medicine. Vol. 5, September 18, 2013, doi: 10.1126/scitranslmed.3006061.
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