Re-Engineering the Intratumoral Myeloid-Macrophage Compartment to Enhance the Response to Radiation and Immunotherapy in Triple-Negative Breast Cancer
Abstract
Breast cancer remains the most common cancer in North America and the second leading cause of cancer death in women. Cytotoxic therapies like radiation therapy (RT) or chemotherapy play an integral part in the treatment of breast cancer, with the majority of triple-negative breast cancer (TNBC) patients receiving cytotoxic therapy sometime during the course of their treatment. The conventional view of cytotoxic therapies has largely focused on the effect of these therapies on the tumor cells themselves. However, recent studies have demonstrated a critical role for the immune system in determining the response of tumors to cytotoxic therapy and multiple studies, including our own, have demonstrated synergy between RT/chemotherapy and immunotherapy. However, despite the improvements in response rates with immunotherapy, more still do not respond, highlighting the need for better understanding and therapies to address immune-resistant tumors. One source of this immune resistance in tumors is thought to be mediated by macrophages, one of the major innate immune cells responsible for regulating inflammation. The objective of this research proposal is to study the impact of restricting the ability of macrophages to activate programming that supports tumor growth by deleting a master transcription factor called GATA-3 in macrophages that regulate pro-tumor programming. The proposal tests the hypothesis that blocking GATA-3 mediated programming in macrophages will enhance anti-tumor immune responses. We test this hypothesis by first looking at the efficacy of chemotherapy, RT, and immunotherapy in mice with GATA-3-deficient macrophages (Aim 1). We then try to understand why there is (or is not) enhanced efficacy of chemotherapy, RT, or immunotherapy by testing whether the effect of treatment is due to different immune cells using agents to remove specific immune cells individually (Aim 2); and testing various key macrophage behaviors to see if there are any differences in inflammatory behavior when the macrophages lack GATA-3. Finally, we focus on testing the idea that macrophages can be used as live cell therapy and that macrophages can be engineered to be deficient in GATA-3 and that these macrophages could enhance the response to therapy similar to the genetically ablated model (Aim 3). We will employ a combination of single-cell sequencing, flow cytometry, and ELISA to follow the changes in the immune profile of tumors following treatment in mice with normal macrophages and mice with macrophages missing GATA-3. The significance of this research is that it will provide insights into the macrophage regulation of tumor immune responses to combined therapy that will lead to new macrophage-based treatments to enhance the efficacy of treatment in breast cancer, and multiple other solid tumors, in which cytotoxic therapies and checkpoint blockade play an integral therapeutic role.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310652
Entities
People
- Stephen Shiao
Organizations
- Cedars-Sinai Medical Center
- United States Army