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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New mechanism for battling influenza

A human protein called TRIM25, which was recently discovered to play an important role in the human immune response to flu infection; and a protein called NS1 present in all strains of the influenza.

TRIM25 acts earlier than previously believed, latching on to a critical and unique flu virus structure like a molecular clamp to keep the virus from replicating as soon as TRIM25 detects this unique structure. NS1 produced by the flu virus can block this function of TRIM25, enabling flu to circumvent the immune response and cause infection.

TRIM25 fought off flu by switching on interferon response- a complex signaling pathway that strengthens cells through the body to fight off pathogens. But not all strains of influenza block this interferon signaling pathway. TRIM25 is also a restriction factor - a special protein present in the fastest-acting arm of the immune system, before spreading infection. Restriction factors lie in wait to detect a virus in the cells.

Flu uses its NS1 protein to evade TRIM25's early flu-fighting response, the researchers infected transgenic cell lines loaded with nonhuman primate versions of TRIM25 with the human influenza virus. They discovered that the cells fought off the virus far better than human versions of the TRIM25 protein.

TRIM25 has the capacity to crush influenza, the researchers combined purified TRIM25 with purified viral ribonucleoproteins (vRNPs)- eight-piece protein chains that house the influenza genome and used state-of-the-art electron microscopy to take pictures of what happened.

They found that TRIM25 appears to swiftly recognize the unique structure of vRNPs and clamps down on them to keep them from replicating inside the cell. Other experiments confirmed that the NS1 protein in flu virus inhibits this function. They also found that TRIM25 is also present in the cell nucleus, which is the same cellular location where flu replication occurs.
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