Harnessing Host Innate Immunity with Innovative Therapeutic Strategies in Triple-Negative Breast Cancer
Abstract
Patients with triple-negative breast cancer (TNBC) are facing outsized challenges to recovery, largely due to lack of effective therapies and high risk of recurrence and metastasis. In recent years, there has been substantial interest and efforts in developing immunotherapy for cancers including TNBC. However, while immunotherapy is particularly effective in melanoma and lung cancer, it is relatively less effective in patients with TNBC. Therefore, it is very meaningful to explore a new target for immunotherapy to combat TNBC. In this project, we will focus on exploiting a type of immune cells called macrophages for treatment of TNBC. This is not only because those macrophages are highly enriched in TNBC tumors, but also because they strongly promote tumor growth. Here, we propose to re-educate these enemies (pro-tumor macrophages) to become our soldiers (anti-tumor macrophages) to combat drug resistance and prevent TNBC lung metastasis. Thus, this project is designed to address two overarching challenges: (1) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival and (2) eliminate the mortality associated with metastatic breast cancer. Modulating macrophages for cancer treatment has proven extremely difficult. We found that activation of a protein called STING reduces pro-tumor activity of macrophages. However, STING agonism alone appears to be ineffective in eliciting sufficient anti-tumor macrophages to combat cancers. More recently, in a pilot study, we noticed that deletion of a gene called STAT3 in macrophages strongly increases anti-tumor activity of macrophages when combining with STING agonism. Therefore, we think optimal activation of anti-tumor macrophages requires both STING activation and STAT3 inhibition. In this project, we will combine a next-generation STING activator with a novel STAT3 inhibitor to harness anti-tumor potential of macrophages for treating drug-resistant models of TNBC. We will also evaluate whether this combination can harness tissue- resident macrophages in the lungs to protect lungs from breast cancer metastasis. Through this project, we will provide novel and crucial proof-of-concept strategies for exploiting macrophages to combat drug resistance and prevent lung metastasis. Our lab has a proven record of translating basic scientific discoveries into clinical trials. The preclinical information derived from this project will guide the rational design of breakthrough clinical trials and thus accelerate the progress in mitigating the burdens of advanced TNBC for our patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310026
Entities
People
- Qiwei Wang
Organizations
- Dana–Farber Cancer Institute
- United States Army