St. Jude Children’s Research Hospital scientists have discovered a way to target the immune system to shrink or eliminate tumors in mice without causing autoimmune problems. Researchers also found evidence that the same mechanism may operate in humans. The study appears in the advance online edition of Nature.
The findings provide a new target for ongoing efforts to develop immunotherapies to harness the immune system to fight cancer and other diseases.
The work focused on white blood cells called regulatory T cells. These specialized cells serve as the immune system’s police force, working to control inflammation and guard against autoimmune and inflammatory disease. Regulatory T cells can, however, interfere with the immune system’s ability to fight cancer.
In this study, investigators identified a mechanism that boosts the ability of regulatory T cells to cause problems by blocking an effective anti-tumor immune response. The same process, however, plays no role in maintaining immune balance or preventing the misguided immune attack on healthy tissue that leads to autoimmune problems, researchers reported. Blocking this mechanism led to the elimination or dramatic reduction of melanoma by the immune system in mice, without causing the autoimmune and inflammatory problems often associated with current cancer-treatment efforts that target immune regulators, scientists said.
“Regulatory T cells are a major barrier to effective anti-tumor immunity,” said the study’s corresponding author, Dario Vignali, Ph.D., vice chair of the St. Jude Department of Immunology. “We have identified a mechanism that enhances the ability of regulatory T cells to put the brakes on the immune response in tumors but plays no role in immune system maintenance. For the first time, we may now have an opportunity to selectively target the activity of regulatory T cells for treatment of cancer without inducing autoimmune or inflammatory complications.”
The mechanism is built around two proteins. One, semaphorin-4a (Sema4a), is carried on the surface of various immune cells that can spark inflammation. The other, neuropilin-1 (Nrp1), is carried on the surface of regulatory T cells.
Vignali and his colleagues used a variety of molecular and cellular techniques to show that Sema4a binding to Nrp1 turns on a biochemical pathway in mouse regulatory T cells that enhances their function, stability and survival. When scientists eliminated Nrp1 on just regulatory T cells, those cells were unable to respond to signals that normally bolstered their anti-inflammatory activity.
When investigators analyzed human regulatory T cells, they found evidence that the pathway may also serve the same role.
In addition, more than 16 months after losing Nrp1 activity in their regulatory T cells, the mice showed no signs of autoimmune or inflammatory complications. “That is significant because mice and humans that lack or have substantial defects in regulatory T cells develop lethal autoimmune disease,” Vignali said.
Knocking out or blocking the activity of Nrp1 on regulatory T cells in mouse models of several human cancers, including the deadly skin cancer melanoma, led to reduced, delayed or complete elimination of the tumors. Blocking Sema4a had a similar anti-tumor effect, researchers reported. “The impact was particularly dramatic in a mouse model of human melanoma,” Vignali said. “Mice lacking Nrp1 on regulatory T cells were almost completely resistant to developing melanoma, but did not develop any autoimmune or inflammatory complications.”
Although investigators have not yet identified which cells carry Sema4a in tumors and boost regulatory T cell function, the scientists did report that immune cells called plasmacytoid dendritic cells (pDCs) provided more than half of the Sema4a in tumors in this study. That was surprising because pDCs make up a very small percentage of immune cells, and there is a long history of suppressive interactions between regulatory T cells and pDCs in tumors, Vignali said. Both cell types are recognized as inducing the immune system to tolerate, rather than attack, tumors.
Researchers also provided new details of how the Nrp1 pathway functions, including evidence that along with bolstering the ability of regulatory T cells to suppress the immune response, the pathway also helps maintain a stable population of regulatory T cells. “This pathway does not just boost regulatory function. It may define how regulatory T cells maintain their identity,” said Greg Delgoffe, Ph.D., a postdoctoral fellow in Vignali’s laboratory. Delgoffe and Seng-Ryong Woo, Ph.D., a former postdoctoral fellow in Vignali’s laboratory, are co-first authors.
The other authors are Meghan Turnis, Cliff Guy, Abigail Overacre, Matthew Bettini, Peter Vogel, David Finkelstein and Creg Workman, all of St. Jude; David Gravano, formerly of St. Jude; and Jody Bonnevier, R&D Systems, Inc., Minneapolis.
The study was funded in part by grants (AI091977, AI039480 and AI098383) from the National Institutes of Health; a grant (CA21765) from the National Cancer Center at NIH; and ALSAC.St. Jude Media Relations Contacts
Summer Freeman | Newswise
NIST scientists discover how to switch liver cancer cell growth from 2-D to 3-D structures
17.11.2017 | National Institute of Standards and Technology (NIST)
High speed video recording precisely measures blood cell velocity
15.11.2017 | ITMO University
The formation of stars in distant galaxies is still largely unexplored. For the first time, astron-omers at the University of Geneva have now been able to closely observe a star system six billion light-years away. In doing so, they are confirming earlier simulations made by the University of Zurich. One special effect is made possible by the multiple reflections of images that run through the cosmos like a snake.
Today, astronomers have a pretty accurate idea of how stars were formed in the recent cosmic past. But do these laws also apply to older galaxies? For around a...
Just because someone is smart and well-motivated doesn't mean he or she can learn the visual skills needed to excel at tasks like matching fingerprints, interpreting medical X-rays, keeping track of aircraft on radar displays or forensic face matching.
That is the implication of a new study which shows for the first time that there is a broad range of differences in people's visual ability and that these...
Computer Tomography (CT) is a standard procedure in hospitals, but so far, the technology has not been suitable for imaging extremely small objects. In PNAS, a team from the Technical University of Munich (TUM) describes a Nano-CT device that creates three-dimensional x-ray images at resolutions up to 100 nanometers. The first test application: Together with colleagues from the University of Kassel and Helmholtz-Zentrum Geesthacht the researchers analyzed the locomotory system of a velvet worm.
During a CT analysis, the object under investigation is x-rayed and a detector measures the respective amount of radiation absorbed from various angles....
The quantum world is fragile; error correction codes are needed to protect the information stored in a quantum object from the deteriorating effects of noise. Quantum physicists in Innsbruck have developed a protocol to pass quantum information between differently encoded building blocks of a future quantum computer, such as processors and memories. Scientists may use this protocol in the future to build a data bus for quantum computers. The researchers have published their work in the journal Nature Communications.
Future quantum computers will be able to solve problems where conventional computers fail today. We are still far away from any large-scale implementation,...
Pillared graphene would transfer heat better if the theoretical material had a few asymmetric junctions that caused wrinkles, according to Rice University...
15.11.2017 | Event News
15.11.2017 | Event News
30.10.2017 | Event News
20.11.2017 | Life Sciences
20.11.2017 | Materials Sciences
20.11.2017 | Life Sciences