Elucidating and Therapeutic Targeting of Prostate Bone Metastasis
Abstract
Prostate cancer (PC), the most common non-cutaneous malignancy in men in the United States (1), often progresses to metastatic castration resistant prostate cancer (mCRPC) in bone. While immune checkpoint blockade (ICB) has yielded meaningful responses across many cancers, clinical trials with anti-CTLA4 or antiPD1 have shown minimal activity in prostate cancer patients. Tumor Immune Micro Environment (TIME) has been increasingly recognized to play essential roles in regulating tumor proliferation, angiogenesis, invasion, metastasis, immune evasion, and resistance to therapeutics but TIME of bone metastases of PC is relatively poorly defined. We hypothesize that the immune suppressive TIME within the bone metastases may exert an important suppressive role on effector immune cells, including CD8 T cells and that depleting bone metastases infiltrating immune suppressive myeloid cells (ISMC) will overcome de novo resistance of ICB therapy against mCRPC. To study the TIME of metastatic PC in bone and dissect the mechanism of ICB failure, we have established syngeneic mouse models in which primary PC cell lines are established from prostate tumor cells of CPPSML mice and injected into C57BL/6 host through intra-femoral injection to generate bone metastasis. We first plan to perform imaging Mass Cytometry (iMC) using 31-panel antibody to comprehensibly define the TIME in this syngeneic model. The iMC results will be validated with IHC co-staining or multiplex IHC staining. Then we will combine ICB with targeted depletion of ISMCs to see if this approach enhances ICB. Specifically, we will use CXCR2 inhibitor, GSK inhibitor, CSF1R inhibitor or anti-IL6 antibody with or without ICB. Finally, emergence of novel cell populations and immune regulators after combination treatment will be subjected to detailed analysis.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2021
- Accession Number
- AD1163019
Entities
People
- Surendra P. Chaurasiya
- Y. A. Wang
Organizations
- The University of Texas MD Anderson Cancer Center