Over 350,000 men die of prostate cancer every year. Although treatment options such as androgen deprivation therapy and chemotherapy are effective in early stages of the disease, once the disease progresses to metastatic castration-resistant prostate cancer (mCRPC), the prognosis is poor, highlighting the need for new and durable treatment options.
In a first-of-its-kind study on dogs with naturally occurring prostate cancer, veterinary scientists at the University of Tokyo have discovered, blocking CCR4 expressing regulatory T cells (Tregs) that infiltrate into tumors and prevent other immune cells from annihilating tumor cells, may be a promising therapeutic strategy for advanced prostate cancer in dogs and a subset of human patients.
“The most significant finding of this study is that a common mechanism (CCL17-CCR4 pathway) is responsible for the intra-tumoral invasion of Tregs in canine and human prostate cancer,” said Shingo Maeda, PhD, assistant professor and a veterinary clinical pathologist at the University of Tokyo, and first author on the paper. “In a preclinical trial in dogs, we showed that CCR4 inhibitors have therapeutic effects by suppressing Treg infiltration.”
The findings are reported in a paper published in the Journal for ImmunoTherapy of Cancer on February 7 (“Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer“).
Maeda said, “We thought that canine and human prostate cancer were similar. Therefore, we hypothesized that there might be a common pathogenesis between canine and human prostate cancer, which led us to this study.” In the study, the scientists explored the pathways used by prostate cancer to evade the immune system and identified an antibody drug that significantly improved survival rates.
Targeting Treg infiltration of tumors is an emerging strategy for immunotherapy in a variety of cancers, but little is known about its efficacy in humans. Although Tregs play an important role in ensuring that immune cells do not attack the body’s own cells, evidence shows some cancer cells can trick Tregs, also called “suppressor” T cells, to inhibit the immune system from recognizing and attacking prostate cancer cells as well.
Tregs that express the transcription factor FOXP3 play a role not only in the suppression of immune response against self-antigens but also inhibit antitumor immunity. FOXP3 controls the rate at which Tregs are produced.
Much of what is known about pathways involved in prostate cancer progression comes from studies in mice. This poses an obstacle for translational efforts since prostate cancers in mice are very different from human cancers in phenotype, gene expression and immune response. Thus far, pre-clinical trials on mice have performed extremely poorly at predicting results in human trials.
“Thankfully ‘man’s best friend’ is once again coming to the rescue,” said Maeda. “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.”
In this study, the researchers used dogs with naturally occurring prostate cancer to study the molecular mechanism that underlies Treg infiltration and to test the efficacy of the anti-Treg immunotherapy.
Using immunohistochemistry, the investigators evaluated and compared tumor infiltrating Tregs in prostate cancers in dogs and humans. Thereafter, using RNA sequencing and protein analyses, the researchers 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.
“We integrated canine and human gene expression data and used a technique called T-SNE [t-distributed stochastic neighbor embedding] to show the similarity between some human prostate cancer patients and canine prostate cancer,” said Maeda. “Although there are hurdles in comparing gene expression across species, we believe that we were able to show the similarity through this method.”
The authors use a clinical dataset of human prostate cancer to compare gene expression in humans and dogs. The researchers conducted a preclinical trial on dogs using mogamulizumab — an antibody drug cloned from other leukocytes (white blood cells) that blocks the CCR4 receptor. Compared to control dogs who did not receive the drug, dogs with prostate cancer that were treated with mogamulizumab showed decreased circulation of Tregs and increased survival with a low incidence of adverse side effects.
Maeda said, “Having demonstrated the use of dogs as a model for advanced prostate cancer studies, we now hope to perform clinical trials and continue the research on the anti-CCR4 antibody drugs in human patients.”