Targeting CD200/CD200R Signaling as a Novel Strategy for the Treatment of Therapy-Resistant Prostate Cancer
Abstract
In the United States, about 268,490 prostate cancer new cases and 34,500 deaths are expected in 2022. Prostate cancer is diagnosed more than any other type of cancer in men and is the second leading cause of cancer-related deaths in the same population. After initial diagnosis of prostate cancer, radical prostatectomy and radiation are used to treat the primary tumors. When cancer recurs, drugs are used to block androgen (such as testosterone) activity associated with the growth of cancerous tissues. For a long time, the treatment has been hampered by drug resistance-the tendency for drugs to stop working over an extended period of time. These androgen receptor signaling inhibitors (ARSI) include enzalutamide (XTANDI), abiraterone acetate (ZYTIGA) and apalutamide (ERLEADA™). Although all drugs are highly effective initially, patients quickly develop resistance to these drugs through mechanisms that are not completely understood. Therefore, there is an urgent need to identify resistant mechanisms to improve the treatment outcome of castration-resistant prostate cancer (CRPC). Over the past decades, the new conceptual and technical advances in immunology have led novel discovery between the immune system and tumors, including prostate cancer. Literatures and our data showed that CRPC treated with enzalutamide may escape the immune surveillance through increasing a cell surface protein named programmed cell death ligand 1 (PD-L1), along with its receptor PD1, which are the widely used targets in immunotherapy for cancer treatment. Unfortunately, clinical trial using enzalutamide and PD-L1 inhibitor (atezolizumab) combination treatment failed to extend the overall survival in CRPC patient and the underlying mechanisms remain unknown. Emerging data from my group found that accompanying with the PD-L1 overexpression in enzalutamide resistant prostate cancer cells, another novel cell surface protein-CD200 was also significantly upregulated. Notably, CD200 expression was negatively regulated by androgen receptor signaling. CD200 and its receptor CD200R works together to suppress immune response in multiple diseases, including cancer. Our data further revealed that enzalutamide treatment not only promoted the CD200 expression in tumor cells but also increased its binding receptor-CD200R population in immunosuppressive cells infiltrating into tumors which may further suppress the immune response. In this project, we hypothesize that the CD200/CD200R signaling activation evades the anti-tumor immunity and causes enzalutamide or anti-PD1/PD-L1 treatment failure in prostate cancer patients. To address the hypothesis, we will investigate the androgen receptor signaling in CD200 regulation and define the role of CD200/CD200R signaling in escaping anti-tumor immunity. We will uncover the underlying mechanisms of CD200/CD200R-directing immune evasion through studying its effects on myeloid-derived suppressor cells (MDSC) which plays an important role in controlling immune response and T cells in cancer patients. We will also find out if using drugs against both PD-L1 and androgen receptor activates CD200/CD200R signaling. Finally, we will determine the CD200/CD200R status in clinical specimens and blood samples from the prostate cancer patients and test the utility of anti-CD200 antibody treatment in combination with anti-PD1/PD-L1 or enzalutamide in animal models. Our proposal will address the 2022 PCRP overarching challenge to Define the biology of prostate cancer progression to lethal prostate cancer to reduce death and Develop treatments that improve outcomes for men with lethal prostate cancer. Identification and characterization of CD200/CD200R signaling involved in immune evasion related to ARSI and anti-PD-L1 treatment will improve current understanding on how patients failed to these treatments and enable us to design strategies for targeted therapies in lethal prostate cancer. This study will contrib
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310144
Entities
People
- Chengfei Liu
Organizations
- United States Army
- University of California, Davis