Immune Regulation of Breast Cancer Metastasis Dormancy
Abstract
Breast cancer patients can develop metastases from dormant tumor cells years after successful primary tumor resection. Clinical studies show that secondary growth is a major rate-limiting step in metastasis given that after successful treatment of the primary tumor, disseminated breast tumor cells often remain “dormant” for many years before resurgence. It remains largely unknown why/how breast cancer cells lay dormant for years and then re-emerge, which is one of the major overarching challenges in breast cancer this proposal aims to address. Our molecular understanding of breast tumor metastasis dormancy has been hindered by the difficulty to detect disseminated dormant tumor cells in vivo. We published the first tumor metastasis mouse model where tumor dissemination can be induced in a controlled and synchronized fashion after primary tumor formation. Building upon this model, we recently established a breast tumor metastasis dormancy mouse model that also fluorescently label individual dormant tumor cells in distant organs. This new model would allow us to study dormant disseminated breast tumor cells and their surrounding niche in an immune-competent mouse breast tumor model. Recent success in activating patient’s own immune systems to help fight cancer has brought immunotherapy to the forefront of treatment options for many cancer types. Ongoing clinical trials show that a type of immunotherapy called immune checkpoint inhibitors yield excellent anti-tumor response in 8%-15% triple-negative breast cancer patients already presenting recurrent metastatic lesions. However, it is unknown whether boosting immune system could prevent re-emergence of metastatic lesions in patients with dormant diseases. Our proposed research aims to understand whether and how dormant metastatic lesions are under immune surveillance. Furthermore, it aims to test whether immunotherapy, such as immune checkpoint inhibitors, could be effective in eliminating dormant tumor cells, thus preventing metastasis recurrence in breast cancer patients. Our proposed research has direct therapeutic implication. Currently, immune checkpoint inhibitors are largely given to breast cancer patients that have failed conventional chemotherapies and present metastatic lesions. Since conventional chemotherapy cannot kill dormant disseminated tumor cells that are not proliferating, many breast cancer patients that are considered “high risk” for metastatic recurrence can only wait and see whether their breast cancer will come back as distant metastases. If our proposed research is successful, it would provide much needed new treatment option for high-risk breast cancer patients. This is especially important for triple-negative breast cancer, for which no other targeted therapy is currently available to prevent metastasis recurrence. A number of immune checkpoint inhibitors are currently in clinical trials for various human cancers and many of them do not present severe side effects. If our research is successful, it could result in immediate clinical trials to prevent metastatic recurrence in high-risk triple-negative breast cancer patients within the next 5 years. In addition, our research also explores new molecular mechanisms that help dormant tumor cells to evade immune surveillance in distant organs. Current immune checkpoint inhibitors generally only generate anti-tumor responses in about 15% breast cancer patients. Uncovering new molecular targets to boost antitumor immunity could significantly improve patient responses to immune checkpoint inhibitors. Therefore, our research could also lead to reducing the mortality associated with metastatic breast cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810055
Entities
People
- Jing Yang
Organizations
- United States Army
- University of California, San Diego