Targeting catecholamines to reverse T cell exhaustion in neuroblastoma
Neuroblastoma is the most common solid tumor found outside the brain in children and remains one of the deadliest childhood cancers. While new treatments have improved outcomes for some patients, many children still experience relapses, especially those with aggressive forms of the disease. One of the most promising areas of cancer research is immunotherapy, which uses the body’s own immune system to fight cancer. In neuroblastoma, a medicine called anti-GD2 immunotherapy has helped some children live longer, but unfortunately, many tumors eventually return. A major reason for treatment failure is that immune cells, particularly specialized white blood cells called T cells, become exhausted when they enter the tumor. Exhausted T cells lose their ability to multiply, release important immune signals, and kill cancer cells. Scientists do not fully understand why this happens in childhood cancers like neuroblastoma. Recent research has discovered that stress hormones called catecholamines, which are produced by nerve cells and some tumors, can weaken the immune system. These hormones work by sending signals through specific receptors on T cells, making them tired and less effective. Since neuroblastoma tumors naturally produce high amounts of these stress hormones, this may be a hidden way these tumors avoid destruction by the immune system. Understanding how this process works could open the door to new and less toxic treatment options for children.
Project Goals
This research project will explore whether blocking stress hormone signals can help the immune system fight neuroblastoma more effectively. We believe that by preventing these harmful signals, we can restore the strength of T cells and improve immunotherapy outcomes for children with this aggressive cancer. Importantly, we plan to test both traditional immune cells and new, laboratory-engineered immune cells called CAR T cells, which have shown early promise in treating some forms of neuroblastoma. Our first goal is to find out if turning off these stress hormone signals inside CAR T cells makes them better at killing neuroblastoma cells in the lab and in animal models. Next, we will investigate how these stress hormone signals affect natural T cells within tumors, using mouse models of neuroblastoma that closely mimic the human disease. Finally, we will test whether combining drugs that block these stress signals with existing immunotherapies, like anti-GD2 and or other types of immune therapies, can improve survival rates in preclinical models. If successful, this work could lead to new treatment strategies that make immunotherapy more effective for children with neuroblastoma. Since many of the drugs we propose to use, called beta blockers, are already FDA-approved for other conditions, these findings could be rapidly translated into clinical trials and offer safer, more accessible options for families battling this difficult disease.
