Research into basic workings of immune system points to way of improving therapies for cancer and chronic infection
October 27, 2016
Note: This study was covered by Boston Globe Media’s Stat,
Harvard Gazette and Harvard Medical School.
Differences in wiring
of “exhausted” and effective T cells indicate possible gene-editing targets
people with chronic infections or cancer, disease-fighting T cells tend to
behave like an overworked militia – wheezing, ill-prepared, tentative – in a
state of “exhaustion” that allows disease to persist. In a paper posted online
today by the journal Science,
researchers at Dana-Farber/Boston
Children’s Cancer and Blood Disorders Center report that, in mice with
chronic viral infection, exhausted T cells are controlled by a fundamentally
different set of molecular circuits than T cells effectively battling
infections or cancer – a finding that suggests a way to increase the staying
power of CAR T cells, a promising form of immunotherapy for cancer.
accompanying study led by researchers at the University of Pennsylvania and
co-authored by Dana-Farber scientists reports that these differences in circuitry
remain largely unchanged by a type of cancer immunotherapy known as checkpoint
inhibition, potentially closing off one avenue of improving this technique.
pair of studies bring renewed focus to the epigenetics of T cells – the
multilayered system of molecular switches, accelerators, and throttles that
controls the activity of genes. Scientists have known for years that the pattern
of genes is different in exhausted T cells than in functional T cells that are
fully engaged in fighting disease, but the actual extent of these differences
has been uncertain.
difference that is clear is that
exhausted T cells express the programmed cell death protein-1 (PD-1), which
commands them not to attack normal, healthy cells, but can also prevent them
from striking at cancerous or chronically infected cells. Blocking PD-1 with
checkpoint-inhibiting drugs – and thereby restoring the cancer-killing zeal of
T cells – has become one of the most successful new approaches to cancer
treatment in nearly a decade. However, it has shown effectiveness in only about
a quarter of cases.
T cells display a variety of functional defects,” says Nicholas
Haining, MD, of Dana-Farber/Boston Children’s, senior author of the new
paper. “They are paralyzed and don’t have the fire-power to destroy cancer or
virally-infected cells. For us, the question in this study was, do exhausted
cells represent a distinct type of T
cell or are they merely a ‘groggy’ version of functional T cells?”
chronically infected mice as their model, the researchers used a new technology
called ATAC-seq to map the regulatory regions of the genome – the sections of
DNA involved in switching genes on and off – in the animals’ exhausted and functional
CD8+ T cells. (CD8+
T cells are programmed to identify and eliminate cancerous and infected cells.)
found the landscape of regulatory regions to be fundamentally different in exhausted
and functional T cells,” Haining says. “There were thousands of instances where
a regulatory region appeared in exhausted T cells but not in their functional
counterparts, and vice versa. This tells us that the two types of cells use
very different wiring diagrams to control their gene activity.”
researchers then tested whether removing a regulatory stretch of DNA that spurs
the production of PD-1 would drive down expression of the protein. Using
CRISPR/Cas9 technology, they snipped out that region and indeed, PD-1
success of this experiment may offer the key to improving CAR T cell
therapy. CAR T cells are T cells that
are removed from a patient, genetically engineered to grow a protein “sensor”
that targets them to tumor cells, and then re-injected into the patient. Although
the retrofitted T cells have demonstrated effectiveness at tracking down cancer
cells, particularly in leukemia, one of the shortcomings of CAR T cells is that
they tend to become exhausted.
The work described in the new study suggests that while T cells are being
engineered to produce the sensor, they could also be re-tooled to delete the
genetic wiring that causes them to express excessive levels of PD-1 or other
exhaustion genes. The resulting CAR T cells would not only be better at
stalking cancer, but also more aggressive about attacking it.
the companion paper, researchers explored whether blocking the PD-1 checkpoint
rewired exhausted T cells to make them, from an epigenetic standpoint, more
like functional T cells. Using chronically infected mouse models, as in the
first study, the investigators found that while such gain of function does
occur briefly, the epigenetic switches from its previous, exhausted state
remain largely unchanged.
suggests that the benefits achieved by checkpoint blockade result from a
transient revving up of exhausted T cells, not a permanent reshaping of their
state,” Haining says.
findings of the two studies point to the need for a comprehensive atlas of the
regulatory regions that are active in exhausted and functional T cells, he
continues. Such a guide would provide targets for rewiring T cells with genetic
engineering or epigenetic drugs to make them more effective cancer killers.
first authors of the study are Debattama R. Sen of Dana-Farber and James
Kaminski of the University of California, Berkeley. Co-authors are R. Anthony
Barnitz, PhD, Ulrike Gerdemann, MD, PhD, Kathleen B. Yates, Hsiao-Wei Tsao,
PhD, Jernej Godec, PhD, Martin W. LaFleur, Flavian D. Brown, of Dana-Farber;
Makoto Kurachi, PhD, and E. John Wherry, PhD, of the University of
Pennsylvania; Pierre Tonnerre, PhD, Raymond T. Chung, MD, and Georg M. Lauer,
MD, PhD, of Massachusetts General Hospital; Damien C. Tully, PhD, and Todd M.
Allen, PhD, of the Ragon Institute of Massachusetts General Hospital,
Massachusetts Institute of Technology, and Harvard University; and Nicole
Frahm, PhD, of the Fred Hutchinson Cancer Research Center.
research was supported by the National Institutes of Health (grants AI115712,
AI091493, AI082630, HG007910, 1R21AI078809- 01, and UM1 AI068618) and the BRAIN
Initiative (grant MH105979).