UVA School of Medicine

says McConnell. "they ranged in age from less than a year to 94 years, and it showed a perfect correlation—a perfect anti-correlation—with age." Based on the finding, McConnell believes that the neurons with significant genetic variation, known as CNV neurons, may be the most vulnerable to dying. and that could explain the idiosyncratic death of specific neurons in different neurodegenerative diseases. People with the most CNV neurons in the temporal lobe, for example, might be likely to develop alzheimer's. More work needs to be done to fully understand what's occurring, McConnell says. so far, he has only looked at neurons in the frontal cortex of the brain, and his studies are limited by the fact that neurons can be examined only after death, so it can be hard to make direct comparisons. But he is excited to expand the scope of his research. "Because i'm collaborating with the lieber institute and they have this fantastic brain bank, now i can look at individuals' frontal cortex for the schizophrenia research and i can look at the temporal lobe in those same individuals," McConnell says. "so now i can really start to map things out more carefully, building an atlas of different brain regions from many individuals." that research could greatly advance our understanding of both neurodegenerative diseases and the cognitive decline that besets us with age, potentially leading to new treatments. "What's really interesting about mosaicism is that it is fundamentally tweaking our assumptions about what nature is, because we've kind of always assumed that every cell in any given individual had the same genome, the same DNa in every cell," McConnell says. "and now we're showing that it's different and what that might mean." UNiversiTy Of virgiNiA reseArChers have discovered a defect in immune cells known as "killer T cells" that explains their inability to destroy cancer tumors. The scientists believe that repairing this defect could make the cells much better cancer killers. Further, they predict their discovery could be used within three to five years to help identify patients who will best respond to cancer therapies. The finding could be a significant boost to the burgeoning field of immunotherapy, which aims to harness the body's immune defenses to defeat cancer. The discovery could also let doctors better predict and assess how well a patient responds to treatment. "For a long time, the presence of immune cells in cancer has been associated with a better outcome in patients, but it's not really been clear why the immune cells haven't been able to control the cancer. What is the cancer doing?" says researcher Timothy Bullock, PhD, an associate professor in the Department of Pathology. "This finding gives us plenty of opportunity to come in with interventions to invigorate these T cells and level the playing field substantially so they're much more competitive." Building Better Cancer Killers Despite their fearsome moniker, "killer" T cells often become inactive in solid tumors. UVA's new research sheds light on why. Bullock and his team determined that these sluggish soldiers suffer from a dysfunctional enzyme, enolase 1. Without it, they cannot use a vital nutrient, glucose. "There is a functional defect in this enzyme that is preventing the cells from breaking down glucose and using it in such a way that they can proliferate and become functional," explains researcher Lelisa F. Gemta. "They don't process it well, and that's what we've been digging into—to find out why do these cells take up glucose but fail to break it down." By amping up the effectiveness of the enzyme, the researchers believe they can make the killer T cells much better at killing cancer. The sluggish soldiers would become much more formidable fighters. The researchers also believe that doctors will be able to examine the enzyme to predict how well a patient will respond to treatment. "I think that there is an opportunity to actually use this enzyme as a read-out for the quality of the T cells that are in the tumor, so that when a physician comes in with a clinical trial we can theoretically analyze how the T cells metabolically compare within the tumor," says Bullock. "It's almost a biomarker of immune function and fitness within the tumors." The research is part of UVA's aggressive efforts to advance the field of immunotherapy. For example, it is conducting a leading-edge clinical trial of an experimental immunotherapy for pediatric acute lymphoblastic leukemia that has resisted other forms of treatment. The approach, known as chimeric antigen receptor T-cell therapy, takes a child's own immune cells and genetically modifies them to make them better at killing cancer. By confronting the defect they have discovered and making these T cells fitter, Bullock hopes that his new discovery will complement such emerging treatments and make them more effective. The finding, he notes, also might be used one day to dampen excessive immune responses, such as are seen in autoimmune disorders. Cancer Killers Finding highlights potential of immunotherapy to defeat cancer Researchers Lelisa F. Gemta and Timothy Bullock, PhD 3 Vitals Spring 2019

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