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Researchers at St. Jude Children?s Research Hospital in Memphis, Tennessee (USA), 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, which was funded in part by the National Institutes of Health (NIH), the National Cancer Center at NIH and ALSAC, was published today in the advance August 4, 2013 online edition of Nature.

Regulatory T-cells
The new research 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.


This pathway … may define how regulatory T-cells maintain their identity…


Mechanism of action
The 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. 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.

?Regulatory T-cells are a major barrier to effective anti-tumor immunity,? said Dario Vignali, Ph.D., vice chair of the St. Jude Department of Immunology and the study?s corresponding author, ?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.?

Two proteins
The mechanism is built around two proteins. One, semaphorin-4a (Sema4a), is carried on the surface of various immune cells that can spark inflammation. Semaphorins are now known to be widely expressed mediators that play significant roles in immune responses and organ morphogenesis. Sema4a, previously identified as an activator of T-cell-mediated immunity, is expressed in endothelial cells, where it suppresses vascular endothelial growth factor (VEGF)-mediated endothelial cell migration and proliferation in vitro and angiogenesis in vivo.[2]

The other, neuropilin-1 (Nrp1), is carried on the surface of regulatory T-cells. Neuropilin-1 is a type I transmembrane protein mainly expressed in endothelial cells and tumor cells. The extracellular domain of Neuropilin-1 contains two complement-binding or CUB domains, two domains with homology to coagulation factors V and VIII, and a meprin or MAM domain. It can form homo- and hetero-oligomers via their MAM domains.

Neuropilin-1 plays a variety of roles in angiogenesis, axon guidance, cell survival, migration, and invasion. It is a receptor for two unrelated ligands with disparate activities, vascular endothelial growth factor-165 (VEGF 165), an angiogenesis factor, and semaphorin/collapsins, mediators of neuronal guidance. Furthermore, Neuropilin-1 binds placenta growth factor-2 and Heparin. As a co-receptor with VEGFR-2 on the surface of endothelial cells (EC), Neuropilin-1enhances VEGF165 binding to VEGFR-2 and EC chemotaxis. The data shows that over-expression of Neuropilin-1 promotes growth and angiogenesis of tumor, as well as proliferation and chemotaxis of leukemic cells. Recent study has revealed that neuropilin-1 is also expressed by dentritic cells (DC) and resting T-cells, and plays a role in initiation of the primary immune response.

Anti-inflammatory activity
Vignali and his colleagues used a variety of molecular and cellular techniques to show that Sema4a binding to Neuropilin-1 turns on a biochemical pathway in mouse regulatory T-cells that enhances their function, stability and survival. When scientists eliminated Neuropilin-1 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 Neuropilin-1activity 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 explained.

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 noted. ?Mice lacking Nrp1 on regulatory T-cells were almost completely resistant to developing melanoma, but did not develop any autoimmune or inflammatory complications.?

Plasmacytoid dendritic cells
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.

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Photo courtesy: St. Jude Children?s Research Hospital in Memphis, Tennessee (USA)

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