Study Finds That Enhancing Certain Immune Cells’ Toxicity in Bone May Present a New Treatment Option for Bone Metastatic Prostate Cancer

Grantee: Leah Cook, PhD
Institution: University of Nebraska Medical Center; Fred & Pamela Buffett Cancer Center
Area of Focus: Cell Structure and Metastasis
Grant Term: 1/1/2020 to 12/31/2023

“Prostate cancer spreads to bone more frequently than to any other place in the body. One type of immune cell, called neutrophils, are generated in bone and have been shown to be important in cancer. My research team predicted that these neutrophils contribute to the cancer’s progression, and we found that neutrophils protect against prostate cancer growth in bone. Current T-cell based immunotherapies for treating prostate cancer have been mostly unsuccessful. The main goal of my research is to identify new immunotherapeutic strategies for treating and curing bone metastatic prostate cancer.”

The Challenge: When prostate cancer spreads (metastasizes), it can spread to many areas of the body but most often spreads to the bone. This type of prostate cancer (called bone metastatic prostate cancer, or BM-PCa) can be very hard to treat: the 5-year survival rate is less than 3%, compared with almost 100% survival for men whose prostate cancer has not spread outside the prostate.

Although some therapies can slow the growth of BM-PCa, there are no treatments that can effectively cure or prevent it.

In their search for new ways to treat BM-PCa, some researchers are turning their focus to immune cells in the tumor microenvironment. They want to understand how the presence of immune cells affects cancer growth and how these immune cells might be used in new treatments.

Research has found that neutrophils, the most common type of immune cell in the bone marrow, seem to affect the growth of primary tumors. Some studies have shown neutrophils help the primary tumor grow, but other studies show they prevent growth instead. There have been few investigations to examine neutrophils in metastatic tumors. Given the abundance of immune cells in the BM-PCa bone microenvironment, the Cook Lab wants to better understand how neutrophils affect cancer progression in bone metastases.

The Research: By studying biopsies from men with BM-PCa, cell culture in the lab, and mice, Leah Cook, PhD, and her lab team found that neutrophils in bone play a significant role in regulating the growth of prostate cancer that’s spread.

Cook’s studies were the first to show the effect of direct neutrophil-prostate cancer interactions on metastatic growth in bones, revealing a role for neutrophils in BM-PCa progression. They discovered that:

Neutrophils have an anti-tumor role in the prostate tumor/bone microenvironment.
An infection or tissue damage causes neutrophils to rapidly replicate and to mobilize from the bone marrow or blood circulation to the site of the problem. Cook’s team learned that prostate cancer bone metastases caused a similar reaction—they stimulate the recruitment of neutrophils, causing them to replicate in the bone marrow and migrate to prostate tumors in the bone.

Neutrophils protect against BM-PCa via STAT5-mediated death of prostate cancer cells.
Cook’s team learned that when neutrophils infiltrate prostate tumors, they initially cause bone metastases to die by blocking the production of STAT5, a protein that manages the growth and invasion of prostate cancer bone metastases.

BM-PCa progresses in bone when cancer cells become able to evade neutrophils.
Her team also found that, eventually, as the tumor progresses, the neutrophils lose their cancer-killing impact. It’s not clear why this happens. It’s possible that the prostate cancer in the bone causes neutrophils to mobilize into blood, allowing prostate cancer cells to evade neutrophils—and thus, evade death. This finding suggests that after the prostate cancer invades the bone, there may be a specific period of time when a new treatment could be most effective in enhancing the toxicity of neutrophils.

Cook’s findings suggest a potential new immunotherapy that could improve how treating BM-PCa is treated. Such a treatment could harness the toxicity of neutrophils in bone to prevent the growth of prostate cancer by regulating neutrophils’ numbers and anti-tumor immune response.

Why does it matter? Cook’s work shows that neutrophils in the microenvironment around bone metastases from prostate cancer have an anti-tumor role.

As researchers continue to learn more about how tumors evade the effects of neutrophils, and about the role of STAT5 in the interaction between neutrophils and cancer cells, these findings could eventually lead to new treatments for BM-PCa.