Dogs are proving to be a much better scientific model for the study of prostate cancer than mice, the typical laboratory animal used for this type of research. When dogs were first used in a breakthrough prostate cancer study, scientists explored the pathways cancer uses to evade the immune system and identified an antibody that dramatically improves survival rates.
The results are described in an article published in the Journal for Cancer Immunotherapy.
Prostate cancer is the most common cancer in men worldwide. In the advanced stages, there are treatments that are effective in most cases for a short time, but eventually the disease progresses beyond being responsive to any curative treatment. The prognosis beyond this point is generally poor.
The researchers hypothesized that a particular type of white blood cells -; regulatory T cells, or Tregs -; may inhibit the ability of the immune system to recognize and therefore attack prostate cancer cells (as well as certain other types of cancer cells). Tregs play an essential role in the immune system, ensuring that white blood cells that recognize and attack foreign cells do not mistake the body’s own cells for foreign cells and attack them. This is why Tregs are sometimes called “suppressor” T cells, because they suppress the immune system and prevent self-attack.
However, it is also believed that certain types of cancer cells can trick Tregs into believing that they shouldn’t be attacked either. Researchers have repeatedly found excess Tregs around these cancers -; a process they call Treg tumor infiltration, likely hijacking other T cells that would otherwise attack the tumor as “foreign.”
Activation (more formally, expression) of the gene that controls the production of Forkhead box protein 3 (FOXP3) is in turn required for the production of Tregs. FOXP3 is a transcription factor, a type of protein that controls the rate at which genes are transcribed. Transcription is what we call the process of taking the genetic information that exists in genes on DNA molecules and packaging that same information into messenger RNA, which then tells the cell’s protein factories to make a particular type of protein that matches the original gene.
Transcription acts much like a memo from a boss telling a worker to start a task, and transcription factors control whether to increase or decrease this transcription process -; in other words, to increase or decrease the production of a protein. And FOXP3 is the transcription factor that controls the rate at which Tregs are made.
So if doctors could develop a way to alter the production of Tregs to reduce it, perhaps this could be used as an immunotherapy for patients with advanced prostate cancers.
The challenge here has been that there is still a lot of guesswork involved, as the precise role of Tregs and the therapeutic potential of their depletion in prostate cancer remains unknown.
This challenge is compounded by the fact that much of what we know here comes from studies and trials involving mice. Mice have been very helpful in getting scientists this far, but preclinical trials using them are extremely poor at predicting outcomes in human trials. Indeed, mice and their cancers are very different from humans in terms of genes, immune responses, and even in terms of the symptoms and progression of their cancers. To go beyond guesswork, better animal models are needed.
“Fortunately, ‘man’s best friend’ is coming to the rescue again,” said Assistant Professor Shingo Maeda, lead researcher on the paper and a veterinary clinical pathologist at the University of Tokyo.
The prostate glands of dogs share many similarities with those of humans. They are actually the only other animal that suffers from a significant incidence of prostate cancer, and the cancer has very similar clinical characteristics, including late onset and cancer growth pattern, to that of humans. »
Shingo Maeda, Assistant Professor, Senior Paper Researcher and Veterinary Clinical Pathologist, University of Tokyo
As a result, the researchers wondered if the natural occurrence of prostate cancer in pet dogs could serve as a bridge between using mice and conducting trials in human patients. Also, since dogs have a shorter lifespan than humans, clinical trials using dogs could be conducted over a shorter period of time.
So the researchers used dogs with naturally occurring prostate cancer to do two things: first, study the molecular mechanism underlying Treg infiltration, and second, test the effect of a anti-Treg treatment.
To perform the first part of the study, the researchers used immunohistochemistry to assess tumor-infiltrating Tregs in dogs and humans and then compared them. This is a laboratory technique that uses antibodies to detect the presence of certain antigens (the part of a pathogen, or in this case a cancer cell, that triggers an immune system response) in a sample of tissue. Next, RNA sequencing and protein analyzes showed a possible link between an increase in tumor-infiltrating Tregs and the production of the chemokine CCL17, a protein that attracts Tregs, which effect this attraction by binding to CCR4, a chemokine receptor (in other words, a lock into which the chemokine CCL17 fits). Finally, a series of human prostate cancer datasets were analyzed to compare gene expression in dogs and humans.
Using this information, the researchers then conducted a preclinical trial in dogs of mogamulizumab -; an antibody cloned from other white blood cells that blocks the CCR4 receptor. Compared to control dogs not receiving mogamulizumab, dogs in the trial showed decreased circulation of Tregs, improved survival, and a low incidence of adverse events.
After demonstrating the use of dogs as a model for advanced prostate cancer studies, the researchers now hope to conduct clinical trials and further research on anti-CCR4 antibodies in human patients.
Maeda, S. et al. (2022) Anti-CCR4 treatment depletes regulatory T cells and leads to clinical activity in a canine model of advanced prostate cancer. Journal for Cancer Immunotherapy. doi.org/10.1136/jitc-2021-003731.