Silvia Formenti, MD

Identifying ways to improve immunotherapy responses so that more patients can benefit from this promising treatment.

Impact

Immunotherapy stimulates a person’s immune system to recognize and destroy cancer cells and is a promising treatment for breast cancer. However, some tumors can evade immune attack. Checkpoint inhibitors (CPI), a type of immunotherapy, work by preventing tumor cells from evading a patient’s immune response. While CPI drugs are approved for treatment of various types of cancers, including some breast cancers, their effectiveness in breast cancer has been disappointing overall. Drs. Formenti and Demaria are investigating ways to improve response to immunotherapies by combining it with radiation treatment. Their research has shown that radiation therapy has the potential to convert a nonresponsive (immunogenically cold) tumor into a responsive (immunogenically hot) one. It does this by generating T cells, the cancer-fighting cells of the immune system. Drs. Formenti and Demaria have taken cells from patients with different types of breast cancer and developed a series of laboratory models that recapitulate the 3D environment of the tumors. Using these innovative models, they are determining ways to enhance responses to immunotherapy with radiation—this will provide a critical step towards developing precision radiotherapy, facilitating its use in combination with immunotherapy as a successful and durable treatment approach for breast cancer patients.

Progress Thus Far

Drs. Formenti and Demaria have shown that radiotherapy not only kills tumor cells but also recruits the immune system to fight cancer. They have found that hormone receptor-positive and triple-negative breast cancers (TNBCs) activate different inflammatory pathways in response to radiation. They identified several genes that are significantly upregulated by radiation in both subtypes. These genes serve important roles in the crosstalk between breast cancer cells and immune cells and studies are underway to further explore their functions. In addition, they characterized their 3D models and obtained additional established 3D models of TNBC. These models provide unique vehicles for further in-depth investigations to optimize the combination of radiation and CPI therapy, tailoring the treatment to specific characteristics of each tumor. Recently, they discovered that radiation therapy induces alterations in how breast cancer cells process specific biomolecules which results in activation of signaling pathways that are also activated by viruses. This suggests that radiation engages viral sensors that then mediate activation of the immune system against the tumor. Others have shown that some commonly mutated genes in breast cancer cells suppress the expression of such viral sensors. The team will pursue the implications of these observations and leverage their 3D models to do this.

What’s next

Drs. Formenti and Demaria will continue to examine how the molecular subtype of breast cancer affects the ability of radiation therapy to induce the immune signals required for an anti-tumor response. Studies are underway to examine the previously identified genes and their role in tumor and immune cell crosstalk. In addition, they will continue to exploit the novel models they have developed in laboratory studies to define ways to monitor an immunogenic response to tumor irradiation, investigate what mutations modulate the ability of radiation therapy to increase breast cancer immunogenicity, and identify ways to improve the ability of radiation to make breast cancer more immunogenic. The new model system provides a powerful way to study the immunogenic effects of radiotherapy in an individual tumor. With this understanding, personalized treatment strategies can be developed to improve the success of immunotherapy for breast cancer.