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
NIH scientists describe potential antibody treatment for multidrug-resistant K. pneumoniae
14.03.2018 | NIH/National Institute of Allergy and Infectious Diseases
Researchers identify key step in viral replication
13.03.2018 | University of Pittsburgh Schools of the Health Sciences
Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...
On 15 March, the AWI research aeroplane Polar 5 will depart for Greenland. Concentrating on the furthest northeast region of the island, an international team...
The world’s second-largest ice shelf was the destination for a Polarstern expedition that ended in Punta Arenas, Chile on 14th March 2018. Oceanographers from...
At the 2018 ILA Berlin Air Show from April 25–29, the Fraunhofer Institute for Laser Technology ILT is showcasing extreme high-speed Laser Material Deposition (EHLA): A video documents how for metal components that are highly loaded, EHLA has already proved itself as an alternative to hard chrome plating, which is now allowed only under special conditions.
When the EU restricted the use of hexavalent chromium compounds to special applications requiring authorization, the move prompted a rethink in the surface...
At the ILA Berlin, hall 4, booth 202, Fraunhofer FHR will present two radar sensors for navigation support of drones. The sensors are valuable components in the implementation of autonomous flying drones: they function as obstacle detectors to prevent collisions. Radar sensors also operate reliably in restricted visibility, e.g. in foggy or dusty conditions. Due to their ability to measure distances with high precision, the radar sensors can also be used as altimeters when other sources of information such as barometers or GPS are not available or cannot operate optimally.
Drones play an increasingly important role in the area of logistics and services. Well-known logistic companies place great hope in these compact, aerial...
16.03.2018 | Event News
13.03.2018 | Event News
08.03.2018 | Event News
16.03.2018 | Earth Sciences
16.03.2018 | Physics and Astronomy
16.03.2018 | Life Sciences