Turning the Immune System Back On: A New Approach to Treating Breast Cancer
For many cancers, immunotherapy has changed the game, helping the body’s own immune system recognize and destroy tumors. But for patients with breast cancer, that breakthrough hasn’t reached its full potential. That’s the challenge Brian Ruffell, PhD, Vince Luca, PhD, and the in Immuno-Oncology team at Moffitt Cancer Center are working to solve.
At this year’s American Association for Cancer Research annual meeting, Ruffell will present research that explores a new way to “turn on” the immune system in breast cancer by targeting a molecule called ENPP1.
Why Breast Cancer Needs a New Approach
Immunotherapy has shown remarkable success in cancers like melanoma and lung cancer, helping immune cells find and attack tumors more effectively often with fewer side effects than traditional treatments. However, in breast cancer, the benefits have been limited.
“Breast cancer patients haven’t benefited from the immunotherapy revolution in the same way,” Ruffell said. “We’re trying to figure out why and how to change that.”
How ENPP1 Acts as a Hidden “Off Switch”
At the center of this research is ENPP1, an enzyme that naturally exists on the surface of many cells in the body. Under normal conditions, it plays important roles in development and overall health. But in cancer, ENPP1 may act as a barrier to the immune system.
“When cells are stressed or damaged, they send out signals to alert the immune system,” Ruffell explained. “ENPP1 breaks down those signals, which can prevent the immune system from recognizing the tumor.”
What Happens When ENPP1 Is Blocked
By blocking ENPP1, Ruffell’s team found that the immune system becomes more active. In preclinical models, T cells, the body’s cancer-fighting cells, were better able to recognize and destroy tumors. In some cases, tumors were completely eliminated.
“We were surprised by how well it worked,” Ruffell said. “In certain models, the tumors were fully rejected.”
Who Could Benefit the Most
Ruffell believes breast cancer patients with BRCA 1 and BRCA 2 benefit the most from this treatment.
This approach may be especially promising for patients with tumors that have defects in DNA repair, such as those with BRCA1 or BRCA2 mutations or many cases of triple-negative breast cancer.
“We think patients with DNA repair defects would benefit the most,” Ruffell said. “These tumors are already producing signals that should activate the immune system. We’re just helping that response break through.”
How This Approach Works with Existing Treatments
The research also shows promise when combined with existing therapies. Targeting ENPP1 enhanced the effectiveness of PARP inhibitors, drugs already used for certain breast cancer patients, and improved responses to immunotherapy.
“When we combined this approach with existing treatments, we saw an enhanced response,” Ruffell said. “That’s where we think this could really make a difference.”
What This Could Mean for Metastatic Disease
Another promising aspect of this research is its potential to impact metastasis, or the spread of cancer. In preclinical studies, blocking ENPP1 appeared to prevent tumors from spreading. “If this approach can impact metastatic disease, that would be incredibly important,” Ruffell said. “That’s where we could see the greatest benefit for patients.”
A New Path Forward for Patients
While still in the early stages, this research represents another way to remove the barriers that prevent the immune system from doing its job. If successful, targeting ENPP1 could help bring the benefits of immunotherapy to more breast cancer patients and open the door to more effective, less toxic treatment options.
