Anti-Treg Treatment Improves Prostate Cancer Outcomes in Canines

In the first use of canines as a model for advanced prostate cancer, Japanese scientists have explored the pathways used by the cancer to evade the immune system and identified an antibody drug that significantly improved survival rates.

Researchers have previously hypothesized that regulatory T cells, or Tregs, inhibit the ability of the immune system to recognize and attack prostate cancer cells. Tregs are meant to keep white blood cells from mistaking the body’s own cells as foreign and attack them, but it is also thought that some types of cancer cells can trick Tregs into thinking that they also shouldn’t be attacked. Researchers have repeatedly found an excess of Tregs hanging around such cancers, likely misdirecting T cells that would otherwise attack the tumor.

For this reason, immunotherapies that dial down production of Tregs could theoretically work for advanced prostate cancer. Such a therapy would depress activation of the gene that controls production of Forkhead box protein 3 (FOXP3), the transcription factor that controls the rate at which Tregs are made. Testing this theory has faced two hurdles; first, the precise role of Tregs and the therapeutic potential of their depletion in prostate cancer remain unknown. Second, preclinical trials using mice have been extremely poor at predicting the results in human trials.

“Thankfully ‘man’s best friend’ is once again coming to the rescue,” says Assistant Professor Shingo Maeda, a lead researcher on the paper and a veterinary clinical pathologist at the University of Tokyo. “The prostate glands of dogs share a great deal of similarities with those of people. They are actually the only other animal that suffers from a significant incidence of prostate cancer, and the cancer has very similar clinical features, including late-age onset and the pattern of cancer growth, to that in humans.”

The team used dogs with naturally occurring prostate cancer to study the molecular mechanism that underlies Treg infiltration and evaluate an anti-Treg treatment. First, the researchers used immunohistochemistry to evaluate and compare tumor-infiltrating Tregs in dogs and humans. RNA sequencing and protein analyses showed a possible link between an increase of tumor-infiltrating Tregs and the production of the chemokine CCL17, a protein that attracts Tregs by binding to CCR4, a chemokine receptor.

A series of human prostate cancer data sets were analyzed to compare gene expression in dogs and humans. Using this information, the researchers conducted a preclinical trial in dogs using mogamulizumab, an antibody drug cloned from other white blood cells that blocks the CCR4 receptor. Compared to control dogs not receiving mogamulizumab, the trial dogs showed decreased circulation of Tregs, improved survival and a low incidence of adverse events.

Having demonstrated the use of dogs as a model for advanced prostate cancer studies, the researchers now hope to perform clinical trials and continue the research on the anti-CCR4 antibody drugs in human patients. The findings are described in the Journal for ImmunoTherapy of Cancer.