Targeting B7x to Overcome Stem Cell-Mediated Immunosuppression in Triple-Negative Breast Cancer
Abstract
Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with poor prognosis. Due to lack of targeted therapy, the systemic treatment of TNBC mainly relies on chemotherapy that has harmful side effects and a high rate of drug resistance. Thus, there is an urgent need to develop safer and more effective treatment for TNBC. The recent development of immune checkpoint blockade has revolutionized cancer therapy, which has led to the award of Nobel Prize to the scientists who discovered immune checkpoint therapy last year. However, most breast cancer patients do not respond to current immunotherapies. TNBC is considered the breast cancer type that most likely to respond to immunotherapy due to its relatively high immunogenicity. Indeed, a recent large-scale clinical trial showed that blocking PD-L1, an immune checkpoint, significantly improves the progression-free and overall survival. However, the response rate is still limited, and the majority of patients did not benefit from the treatment. The limited response to the existing treatments highlights the need to understand the immune suppressive mechanisms in breast cancer and to develop new strategies targeting other immune checkpoints to improve the immunotherapy of human breast cancers. This proposal stems from a productive collaboration between the Initiating Principal Investigator (PI) and the Partnering PI. These two PIs have expertise in distinct, but complementary research areas, which will be of great benefit for the program. Our preliminary studies uncovered a novel role of the breast stem cell program in controlling the immune checkpoint protein B7x production and suppressing immune response in TNBC. B7x, originally discovered by us, is a much less studied immune checkpoint that has been shown to be produced at high levels and associated with immunosuppression in TNBC. Our studies have found it has very different mechanisms of action from other currently targeted immune checkpoints and provides excellent targets to develop new immunotherapies. In this proposal, we will elucidate the function and mechanism of action of this important immune checkpoint in TNBC. Furthermore, we have already generated therapeutic antibodies against B7x and will develop anti-B7x immunotherapy against TNBC. Achieving the above goals will have direct impact on at least two Overarching Challenges: (1) Identify what drives breast cancer growth; determine how to stop it. (2) Revolutionize treatment regimens by replacing them with ones (e.g., immunotherapy) that are more effective, less toxic, and impact survival. This proposal is based on original findings that have recently emerged from our ongoing long-term efforts to understand the biology and therapeutic potential of new immune checkpoints and stem cell pathways in breast cancer. A successful outcome of this project will uncover a novel immunosuppression mechanism and develop new immunotherapy against TNBC. Because B7x is also expressed in other breast cancer types, biological insights and therapeutic tools generated here can potentially have wide applications.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010027
Entities
People
- Wenjun Guo
Organizations
- Albert Einstein College of Medicine
- United States Army