Reprogram cancer cells into immune defenders

By reprogramming tumor cells to become bodyguards, Filipe Pereira and his colleagues hope to improve current cancer treatments.

Right now, some immune systemIts most important players, the dendritic cells, are patrolling your body in search of foreign substances. If they find something suspicious, they split it into smaller pieces, called antigens, are presented to the body’s lymphocytes, also known as killer cells of the immune system. This is how killer cells learn which threats to look for and fight.

What if dendritic cells could be generated? Pereira, a professor at Lund University, decided to give it a try.

“Through cloning the sheep Dolly, we learned that the nucleus of somatic cells (all cells except gametes) contains all the information needed for the cell to develop into any cell. The fate of the cell is determined by which genes are expressed in the nucleus. If we adjust gene expression, we can make a cell transform into a completely different cell. The challenge is knowing which molecules need to be added in order for the cell to be reprogrammed exactly how you want it. Based on this concept of reprogramming, says Pereira, I decided to deal with dendritic cells.

It worked. In 2018 and 2022, Pereira and his research team published their results: code that enables the reprogramming of mouse and human connective tissue cells, such as skin cells, into immunoprotective agents. —dendritic cells.

Three Trojan molecules turned out to be the answer

The process of reprogramming the cells into dendritic cells with the same antigen-presenting and detection capabilities as native dendritic cells took 8 days.

“We succeeded by adding three molecules, called transcription factors. I usually call these molecules ‘three Trojan horses,'” Pereira said.

Dendritic cells are also capable of detecting cancer cells in the early stages of tumor growth. But when cancer cells divide and mutate, they disguise themselves. As a result, the cancer cells avoid detection, which means that the dendritic cells cannot do their job.

However, Pereira had an idea. What if these molecules could be used to reprogram cancer cells into dendritic cells? In other words, a kind of cancer gene therapy.

“Usually, when we talk about gene therapy, we mean the repair of a defective or damaged gene in a person. Instead, we mean the use here. Gene therapy to reprogram cancer cells, forcing them to unmask themselves,” Pereira said.

Patrol cells reveal tumor cells

How it works? Using three Trojan molecules, cancer cells are reprogrammed into dendritic cells reveal the true identity of the tumor to the immune system. This strategy has the potential to improve existing cancer therapies such as immunomodulatory therapy (which won the 2018 Nobel Prize in Physiology or Medicine). Simply put, this involves blocking the molecular brake that prevents killer cells from doing their job. This allows the immune system to exert its full potential against the cancer cells.

Pereira specially studied melanoma and head and neck cancers, which are known to have moderate to high mutation rates.

“The new checkpoint therapy is effective in 20-30% of patients with melanoma. Our hope is that our findings will complement this treatment, making it more effective.” , Pereira said.

That is an advantage if the tumor has accumulated mutations.

“When we tested it in mice, we found that the majority of the 15 treated tumors showed reduced growth. Two of the mice were completely cured. This makes us want to go this far. more and we hope to do that.” clinical trials over the next few years, even if the road ahead isn’t entirely flat,” Pereira said.

The team is currently working on how to address the delivery of Trojan molecules to tumors. One way is virus vectorstake advantage of the effective mechanism of the virus to enter the cell but still eliminate all viral components that can cause disease and the ability to multiply.

Pereira argues that the growing enthusiasm for gene therapies is due to recent successes in the field.

“It gives hope to patients with diseases that cannot be treated by current traditional treatments. At the same time, there are many challenges ahead. The Legal framework are not yet ready for these new therapies, the production is demanding and the costs are high, often higher than that of traditional drug development. But like I said, if it was easy, it would have been done. Right?” Pereira said.