Project 2 – Targeting WNT5A-Mediated Crosstalk with the Tumor Microenvironment in ACC
Investigators: Kaitlin Basham, Stéphane Angers, Fiemu Nwariaku & Melissa Reeves (University of Utah - Huntsman Cancer Institute - University of Toronto)
Disease information: Adrenocortical carcinoma (ACC) is an aggressive cancer with limited treatment options. For patients and families facing this diagnosis, the development of new treatments has been frustratingly slow. While immunotherapy has greatly improved outcomes for many other cancers, it has not yet delivered meaningful benefit for most patients with ACC. Fewer than 15% of patients respond, and even those responses are often short-lived. Understanding why immunotherapy does not work in ACC – and how to make it work – is one of the most urgent challenges in the field.
Background: Our research focuses on a major barrier to immunotherapy success – the tumor’s ability to shut down the immune system. ACC tumors create a local environment that prevents immune cells, especially cancer-fighting T cells, from entering the tumor and doing their job. We have identified a protein made by tumor cells, called WNT5A, as a key driver of this immune shutdown.
Using a laboratory model that closely resembles human ACC, we found that WNT5A acts like a gatekeeper to block protective immune cells from getting into the tumor. In both our model and human patient data, high levels of WNT5A are linked to weaker immune activity and worse outcomes. These findings suggest that WNT5A is a promising new treatment target. Our goal is to develop new ways to block WNT5A activity, restore immune function, and improve response to immunotherapy.
Key Objectives: Our long-term objective is to develop a drug that can be used in patients to block WNT5A. To achieve this goal, our project has three Key Objectives:
- Identify which receptor WNT5A uses in adrenal tumors;
- Understand how WNT5A inhibits immune cells;
- Test whether blocking WNT5A can make immunotherapy more effective.
Expected results, knowledge utilization, and impact: We expect that inhibiting WNT5A will increase the recruitment of cancer fighting immune cells into the adrenal gland and enhance the efficacy of immunotherapy. By identifying the precise receptor that WNT5A signals through, we will be able to test new drugs developed by our team that block individual receptors, thereby avoiding the serious side effects that have been previously observed with broad-acting WNT pathway inhibitors. If successful, this work could lead to new combination treatments that make immunotherapy effective for more ACC patients. This will not only address an unmet need for new ACC therapies, but also provide insights that can inform other cancers where the immune system is impaired.