Regulation of Prostate Skeletal Bone Metastases by TIM-3-Dependent Efferocytosis
Abstract
Nearly 100 percent of advanced prostate cancer patients develop bone metastases, which are a devastating terminal aspect of this cancer. Daily, millions of cells die in our bodies activating signals that recruit normal immune cells, called macrophages, to clear dead cells and maintain normal tissue health. Interestingly, millions of tumor cancer cells also die during tumor progression, yet little is known about what happens when macrophages clear away dead cancer cells. A previous study from our laboratory found that, when normal macrophages clear away dead prostate cancer cells (a process called efferocytosis), they produce factors that are toxic and support further tumor growth. New knowledge of the specific pathways in macrophages that trigger this reaction will be critical to develop new therapeutic strategies to prevent and treat prostate cancer. Our laboratory has identified a specific mediator on macrophage cells that links to the surface of a dead cell, facilitating recognition for the macrophage to know it needs to be cleared away. This specific mediator, T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), interacts with another mediator called carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1). CEACAM1 also signals through cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2. This interaction then induces a signaling cascade that results in the production of factors that suppress the immune system and hence promote cancer progression and metastases. Preliminary data in this proposal suggest that macrophage-mediated efferocytosis of dead prostate cancer cells increases TIM-3 activity and the production of mediators that support the tumor. Blockade of TIM-3/CEACAM1interaction and inhibition of SHP-1/SHP-2 reduced significantly TIM-3 activity in efferocytic macrophages. Single-cell RNA sequencing of efferocytic macrophages identified upregulated genes related to immunosuppression. Moreover, significantly higher numbers of TIM-3 positive efferocytic macrophages were found in bone marrow samples of grade 5 (advanced) prostate cancer patients. Finally, TIM-3 is active in macrophages within metastatic bone tumor in human tissue. Together, our data propose TIM-3 as the central regulator of immunosuppression and tumor growth in bone metastases through macrophage-mediated efferocytosis of dead prostate cancer cells. Further studies are necessary to identify the molecular mechanisms downstream of the TIM-3/CEACAM1/SHP-1/2 signaling pathway and to address how these mechanisms promote bone tumor growth. This proposal will contribute to the overarching challenge of defining the biology of lethal prostate cancer to reduce death by understanding the molecular mechanisms of macrophage efferocytosis of apoptotic prostate cancer cells in the bone environment. In addition, this study will identify new targets responsible for bone tumor growth progression and inhibitors that could be used as coadjuvant therapies to diminish the lethality of prostate skeletal bone metastases. The knowledge gained about the molecular mechanisms activated by TIM-3 will be useful to design or use molecules that are already known to diminish the immunosuppressive and pro-inflammatory effect of macrophage efferocytosis in the bone microenvironment to prevent or control prostate skeletal bone metastases without suppressing the clearance of apoptotic prostate cancer cells. Dr. Mendoza’s long-term career goal is to become an independent researcher in understanding the key tumor immune mechanisms that contribute to prostate cancer metastases. In order to achieve this goal, it is fundamental that her training as a postdoctoral fellow is carried out in one of the best research environments together with the guidance and support of experienced mentors. Dr. Laurie McCauley and Dr. Hernan Roca are highly recognized researchers in the prostate cancer field and have an extensive record for training postdoctoral fe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110122
Entities
People
- Leidy Mendoza Reinoso
Organizations
- United States Army
- University of Michigan