A new study by University of Arizona Health Sciences researchers found that an immunotherapy previously shown to be ineffective against prostate cancer may have therapeutic potential when combined with a synergistic treatment approach.

The paper was published in the journal Cancer Immunology Research.

A research team led by U of A Cancer Centre member Noel Warfel, PhD, identified a way to sensitise prostate tumours to immune checkpoint inhibitors, a type of immunotherapy.

They used a specific protein inhibitor to reprogram tumour-associated macrophages – white blood cells that are hijacked by cancer to suppress the killing of cancer cells instead of performing their usual role in working with T cells to fight disease.

The co-targeted therapeutic approach is a promising new area of cancer research, and this is the first time it has been tested for prostate cancer.

“When we look at the big picture and the collective data, we have solid evidence that this is a strategy that could improve the efficacy of immunotherapy in prostate cancer,” said Warfel, the study’s supervising author and an associate professor at the U of A College of Medicine – Tucson.

Immunotherapy works by helping T cells – a type of immune cell that recognises and destroys threats – identify and kill cancer cells.

To grow and spread, cancer cells must evade the immune system.

They do so by producing checkpoint proteins that bind to T cells and stop them from killing cancer cells.

Immune checkpoint inhibitors block checkpoint proteins, allowing the immune system to destroy cancer cells.

“Immune checkpoint inhibitors have really changed the treatment paradigm for many types of cancer, but this approach has not previously been effective in treating prostate cancer, and we don’t know why,” Warfel said.

The answer might lie with protein kinases – enzymes that speed up chemical reactions in the body.

Specifically, PIM1 kinase is a cancer-driving protein that is known to amplify signals that promote cell growth and the proliferation of cancer cells.

“Kinases are part of a complex process that allows cancer cells to transmit signals,” said the study’s first author, Amber Clements, PhD, a former graduate student in the U of A Cancer Biology Programme who is now a postdoctoral research associate at the College of Medicine – Tucson.

“PIM kinases also help cancer cells migrate and survive, but we did not expect that they would be so important in the tumour-immune microenvironment.”

Warfel’s team discovered that the overexpression of PIM1 kinase in tumour-associated macrophages was a driver of resistance to immunotherapy.

By inhibiting PIM1 kinase in conjunction with an immune checkpoint inhibitor, Warfel’s team was able to reduce cancer tumour growth in laboratory and animal models of prostate cancer.

“What we found surprising in our study was that blocking PIM1 specifically in macrophages reduced tumour growth in our models of prostate cancer,” Warfel said.

“By blocking PIM activity, we increased the presence of macrophages and tumour inflammation, which increases the proliferation of T cells in the prostate and improves their ability to destroy the prostate cancer cells. What we’re seeing is that inhibiting PIM while at the same time using immune checkpoint inhibitors creates a synergistic effect that reduces tumour growth.”

Warfel added that PIM inhibitors are actively being tested to combat cancer and other diseases.

He is hopeful that continued efforts in this project will ultimately lead to a clinical trial at the U of A Cancer Centre.

According to the American Cancer Society, about 1 in 8 men will be diagnosed with prostate cancer during their lifetimes.

Prostate cancer is the second most common cancer in men, after skin cancer, in the United States.

In addition to Warfel and Clements, co-authors include eight U of A Cancer Centre members and three graduate students from the Cancer Biology Programme, plus collaborators from outside organisations, including Caris Life Sciences, Karmanos Cancer Institute and the University of California, San Diego.

Source: University of Arizona Health Sciences