Artificial molecules boost cancer therapy

Researchers at EPFL have created artificial molecules that can help the immune system to recognize and attack cancer tumors. Immunotherapies are breakthrough treatments that stimulate the patient's immune cells to attack the tumor through the recognition of tumor antigens.

Dendritic cells are specialized immune cells whose role is to capture antigens from foreign bodies and present them to the immune system's killer T cells, which will then attack and destroy the invaders. For the vaccine, dendritic cells are taken out of the patient, "force-fed" with tumor antigens, and finally re-injected back into the patient. The idea is to facilitate the ability of the dendritic cells to prime killer T cells against the tumor, which is notoriously skilled in concealing itself from the patient's immune system.

Dendritic cell vaccines have achieved some clinical success but not without several limitations. For example, the tumor antigens used to "feed" the dendritic cells are generally not taken from the patient's tumor but from lab-grown cancer cells that are only partially similar to those of the patient. This can limit the power of the vaccine because its tumor antigens may differ from those of the patient's tumor, meaning that the killer T cells would not be properly activated to recognize and attack the tumor.

A group of researchers led by Michele De Palma at EPFL have now created artificial receptors called EVIR (extracellular vesicle-internalizing receptors), which enable the dendritic cells in the vaccine to selectively and efficiently capture antigens from the actual patient's tumor. This is achieved by inserting the EVIR into the dendritic cell, where it recognizes a protein on small vesicles called exosomes.

Exosomes are profusely released by the tumor and contain a variety of tumor antigens. They are also increasingly implicated in the promotion of metastasis and other processes that may facilitate the growth and spreading of cancer. By capturing exosomes coming from tumors, the EVIR helps the dendritic cells to precisely acquire tumor antigens from the cancer cells. The dendritic cells then present these antigens more efficiently to killer T cells, thus amplifying the patient's immune response against their tumor.

Imaging techniques also revealed that EVIRs promote the direct transfer of tumor antigens from the exosome surface to the outer membrane of the dendritic cell. This is a fascinating and unconventional route for antigen presentation to T cells,  which does not require complex and rate-limiting molecular interactions inside the dendritic cell.

The EVIR technology can intercept a natural phenomenon - the release of exosomes from tumors - to the patient's benefit, it exploits pro-tumoral exosomes as selective nanocarriers of tumor antigens, making them available to the immune system for cancer recognition and rejection. Although the new technology has the potential to increase the efficacy and specificity of dendritic cell vaccines, further pre-clinical work is required before it can be translated into a cancer treatment.
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How immune system's organ regenerates

A molecule called BMP4 that plays a key role in the thymus's extraordinary natural ability to recover from damage. Dr. Jarrod Dudakov of Fred Hutchinson Cancer Research Center, one of the study's leaders, talks about the importance of the thymus, the discoveries he and his colleagues have made about how it regenerates. The researchers hope to translate their work into new therapies to improve the function of the immune system in old age and make immunotherapies more effective.

The thymus is like a boot camp for new recruits to the immune system. From their birthplace in the bone marrow, immature white blood cells go to the thymus to mature into disease-killing machines. A healthy, active thymus gets you a diverse set of different T cells, each equipped to recognize and kill a slightly different foreign target. Thus, the organ is critical for a strong immune system that's ready to prevent any threat.

The thymus is sensitive to damage from everything from infections to life stress, it is also naturally resilient. Its power to bounce back from injury, however, fades with age, and it can take a serious hit from certain aggressive cancer therapies. BMP4, the molecule identified in the team's new study, is only the second known driver of natural thymic regeneration.

 The researchers found that BMP4 is produced by certain cells lining the inside of the organ. That molecule signals other cells of the thymus to turn on genes that promote development and repair.
Now, the team is working to figure out whether there's a master trigger that activates the whole regeneration process and then translate that knowledge into new therapies that help patients.
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Genome editing improves T-cell for cancer immunotherapy

Researchers have discovered a way to boost the cancer-destroying ability of the immune system's T-cells, offering new hope in the fight against a wide range of cancers. Using CRISPR genome editing, the team took the genetic engineering of killer T-cells one step further by removing their non- cancer specific receptors and replacing them with ones that would recognize specific cancer cells and destroy them.T-cells engineered to fight cancer had two kinds of receptors – the therapeutic one that was added in the lab, and their own naturally existing one.

Since there is only limited 'space' on a cell for receptors, cancer-specific ones need to compete with the cell's own receptors to perform their function. More often than not, the cell's own receptors win that competition, and leave 'space' for only a very limited number of newly introduced, cancer-specific receptors, which means that T-cells engineered with the current technology never reach their full potential as cancer killers. The T-cells we made using genome editing do not have any of their own T-cell receptors left, and therefore the only receptor they can use is the one specific for cancer. As a result, these cells can be  better at seeing and killing cancer than the cells prepared using the current methodology.

T-cells are a part of the immune system that helps human to fight off bacterial and viral infections, such as the flu virus. Some T-cells are also able to attack cancer cells. Augmenting and harnessing the anti-cancer activity of the body's own T-cells has led to the development of so-called immunotherapies which are now transforming the field of cancer treatment, even giving hope to patients with final stage disease.

The team believe that in time new improvements in gene editing technology are set to revolutionise cancer immunotherapy, making the treatments, which are unprecedented in their effectiveness, applicable to wider cohorts of patients suffering from different types of the disease. The improvement in the sensitivity of cancer recognition that can be achieved by editing out the existing natural receptor and then replacing it with one that sees cancer cells is remarkable. Immunotherapy-harnessing the body´s own immune cells has become the most potent and promising new treatment for a range of cancers and represents one of the biggest breakthroughs in cancer treatment.
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