The importance of the bone marrow in hematopoiesis has been well documented. However, the function of bone marrow in tumor T cell immunity is not well understood. Regulatory T cells (Tregs), dendritic cells (DOs) and effector T cells are found in the bone marrow. In this proposal, we focus on the cross-talk between Tregs, DCs and bone cells in the context of tumor bone marrow metastasis. We hypothesize that tumor bone marrow environmental cells provide cellular and molecular signals for Treg expansion, and that Tregs contribute to bone immunopathology in tumor bone marrow metastasis. Receptor activator of NF-kB (RANK) and its ligand RANKL signals are implicated in Treg expansion in diabetes and ultraviolet-induced immune suppression. We hypothesize that DCs in the tumor associated bone marrow environment provide specific molecular signals for Treg expansion, and RANK/RANKL is the molecular pathway mediated Treg expansion. The numbers and function of osteoblast and osteoclast control the balance between bone deposition and resorption. We hypothesize that bone marrow Tregs promote bone deposition, the main bone pathology of prostate cancer bone metastasis, through inhibiting osteoclast differentiation and function, and tilting the balance toward osteoblasts.
Our specific aims are:
Aim 1 : To test the hypothesis that Tregs expand in the tumor associated BM in mouse model Aim 2: To test the hypothesis that tumor associated BM DCs induce Treg expansion in mouse model
Prostate cancer is the most frequently diagnosed cancer in menand the second leading cause of cancer death among men in theUnited States. The most common site of prostate cancer metastasisis the bone. What defines the cellular and molecular predilection for tumors to metastasize to bone marrow is not well understood. Once prostate cancer metastasizes to bone marrow, the treatment options are limited. In this project we focus on human and mouse epithelial cancer and bone marrow metastasis. We will define the immunopathological mechanism of cancer bone marrow metastasis. Our study will advance our knowledge in the biology of immune cells, bone marrow and prostate cancer. Targeting the cellular and molecular mechanisms relevant for prostate cancer bone marrow function will reduce or/and prevent prostate tumor bone metastasis. Thus, the study is relevant to human cancer pathology and treatment.
| Nagarsheth, Nisha; Wicha, Max S; Zou, Weiping (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17:559-572 |
| Zou, Weiping; Wolchok, Jedd D; Chen, Lieping (2016) PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: Mechanisms, response biomarkers, and combinations. Sci Transl Med 8:328rv4 |
| Zhao, Ende; Xu, Huanbin; Wang, Lin et al. (2012) Bone marrow and the control of immunity. Cell Mol Immunol 9:11-9 |
| Kryczek, Ilona; Wu, Ke; Zhao, Ende et al. (2011) IL-17+ regulatory T cells in the microenvironments of chronic inflammation and cancer. J Immunol 186:4388-95 |
