Project 1 - Targeting TADA2B-SAGA activity to overcome immune cell evasion in ACC
Investigators: Kleiton Borges, David Breault, Vasileios Chortis & Cristina Ronchi (Boston Children’s Hospital - Harvard Medical School - University of Birmingham)
Adrenocortical carcinoma (ACC) is a rare but aggressive cancer of the adrenal gland with poor survival rates and few treatment options. In most patients, available treatments work for only a limited time before the cancer returns and spreads. Immunotherapy, which helps the immune system recognize and attack tumors, has transformed treatment for many cancers but has shown limited success in ACC. One reason may be that ACC tumors can hide from the immune system, although the underlying mechanisms remain poorly understood.
Using a new mouse model that closely mirrors aggressive, immunotherapy-resistant human ACC, we identified a protein called TADA2B that helps tumors evade immune attack. TADA2B is part of a larger protein complex known as SAGA, which helps control how genes are turned on and off. We found that removing TADA2B activates immune pathways and makes tumors more responsive to immunotherapy. Importantly, drugs that target other components of the SAGA complex can reproduce many of these effects, pointing to a promising new therapeutic strategy.
This project will investigate how targeting TADA2B-SAGA activity strengthens anti-tumor immunity and whether the same mechanisms operate in tumors from ACC patients. Our goal is to develop new ways to help the immune system recognize and eliminate ACC, ultimately leading to more effective treatments for patients with this devastating disease.