Immune Privilege of the Hematopoietic Stem Cell Niche in the Bone Marrow Shields Metastatic Prostate Cancer from Immunity
Abstract
Over 70% of patients with advanced prostate cancer display bone or bone marrow metastases that are strongly resistant to various treatment approaches. For example, a newly developed immune therapy, anti-PD1 antibody, was effective against various cancers, but not against prostate cancer following bone metastases. It remains unknown why prostate cancer shows therapeutic resistance following bone metastases. Importantly, we recently discovered that some lymphocyte subset with powerful immune suppressive potential, called regulatory T cell, accumulate on the bone surface and create tiny spaces of “sanctuaries,” where blood stem cells are shielded from the immune system. Because stem cells and cancer cells share many features, including cell migration mechanisms, we hypothesize that prostate cancer preferentially metastasizes to this sanctuary for blood stem cells on the bone surface, where cancer cells hide from the immune system or immune therapy. The proposal aims to test this hypothesis and further seek to develop a novel therapy to disrupt the sanctuary for cancer and allow the immune system or immune therapy to eradicate metastatic prostate cancer. We will use a recently developed, novel mouse model in which prostate cancer frequently homes to the bone marrow. Using the combination of this mouse model and a cutting-edge microscope, called a two-photon microscope, which enables direct visualization of individual cancer cells in live mice, we will test whether prostate cancer cells home to the stem cell sanctuary on the bone. Next, we will disrupt this stem cell sanctuary by using various genetic or pharmacological approaches to modulate regulatory T cells or other immune suppressive cells within the bone marrow and test whether the breakdown of the sanctuary leads to loss of prostate cancer and improves the efficacy of immune therapy. Finally, by using a novel genomic approach, called RNA sequencing, we will obtain a complete profile of the cellular RNA composition in regulatory T cells isolated from the stem cell sanctuary and seek to discover new treatment targets to inhibit regulatory T cells and destroy this oasis for cancer. Completion of the study will establish an unprecedented paradigm that cancer cells home to the sanctuary for stem cells, where cancer cells escape from the immune system, leading to therapeutic resistance. Successful results from our study will lead to novel therapeutic strategies for advanced prostate cancer patients with bone metastases. Immediately after completion of the proposed study, we anticipate initiation of the clinical trial to test the efficacy of several drugs for patients with advanced prostate cancer. This trial will take 3 to 5 years to complete.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810191
Entities
People
- Joji Fujisaki
Organizations
- Columbia University
- United States Army