Mechanism Offers Promising New Approach for Harnessing the Immune System to Fight Cancer
Scientists at St. Jude Children’s Research Hospital 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 was published online today in Nature.
The findings provide a new target for ongoing efforts to develop immunotherapies to harness the immune system to fight cancer and other diseases.
In the study, investigators identified a mechanism that boosts the ability of regulatory T cells to cause problems by blocking an effective antitumor 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, the investigators said.
“Regulatory T cells are a major barrier to effective antitumor immunity,” said the study’s corresponding author, Dario Vignali, PhD, 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.”
Sema4a–Nrp1 Pathway
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.
Dr. Vignali and 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 serve the same role.
Dramatic Antitumor Effects
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,” Dr. Vignali said.
Knocking out or blocking the activity of Nrp1 on regulatory T cells in mouse models of several human cancers, including melanoma, led to reduced, delayed, or complete elimination of the tumors. Blocking Sema4a had a similar antitumor effect, researchers reported. “The impact was particularly dramatic in a mouse model of human melanoma,” Dr. 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 provided more than half of the Sema4a in tumors in this study. That was surprising because plasmacytoid dendritic cells make up a very small percentage of immune cells, and there is a long history of suppressive interactions between regulatory T cells and plasmacytoid dendritic cells in tumors, Dr. 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, PhD, a postdoctoral fellow in Dr. Vignali’s laboratory.
The study was funded in part by grants (AI091977, AI039480, and AI098383) from the National Institutes of Health (NIH), a grant (CA21765) from the National Cancer Center at NIH, and ALSAC.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
