In a paper published in Cell reports, a team of researchers from the National Laboratory for Accelerator Departments at the Department of Energy SLAC and Stanford University have discovered unique features of a protein called VISTA that protects cancer cells from being hit by the immune system. A better understanding of how this protein works can guide the design of treatments that target these proteins, infiltrating it into the first defense of cancer.
The human body is made up of trillions of cells that are constantly being created, destroyed and replaced by new, like shovels of grass on the lawn. But when cells start to grow and divide uncontrollably, like boring weeds, they can form a solid mass called a tumor. If it is cancer, this tumor can deepen its roots and spread to other parts of the body.
The solution seems clear enough. Just as anyone can disappoint a garden, the immune system can invade these diseased cells and squeeze the cancer into the bud. But tumors have a secret weapon: the ability to cloak, using special "checkpoints" proteins, such as VISTA, and disguised as normal, healthy grass.
"When tumor cells appear, they are recognized as foreign and released from the immune system by specialized cells known as T cells," says Ennifer Kochran, a professor of bioengineering at Stanford University. "But the surface markers of the cells surrounding the tumor known as 'immune checkpoints' have proved invisible to a variety of veils to protect the tumor from recognizing and destroying the immune system."
Removing the cloak of invisibility
FDA-approved antibodies that take away this invisibility cloak and release attacks on the immune system of tumors have shown tremendous power in treating different types of cancers because they allow the immune system to find and destroy cancer cells without toxic effects. But because of a lack of information on how checkpoint proteins work, these drugs are only effective for about a quarter of patients.
Foremost, the team, led by Cochrane, Poshu Huang, a Stanford bioengineering professor, and Nishant Mehta, a Stanford doctor. The candidate, in collaboration with Irimpan Mathews, a researcher at Stanford Synchrotron Radiation Lights (SSRL), was able to map the VISTA high-resolution structure, which required a combination of computer and experimental techniques.
To better understand its structure, the researchers crystallized the VISTA molecules and then measured how the crystals scattered the X-rays of one of the specialized SSRL rays. When researchers analyzed the data using computational tools, the patterns formed when X-rays irradiated the crystals allowed them to map the shape and detailed atomic structure of the protein, as well as its epitope, the part of the molecule that the immune system can recognize and target.
"This research was only possible because of collaboration between experts in molecular engineering, computer protein design and structural biology," says Matthews.
Defeat the defense
To follow up on this research, Mehta hopes to use what they have learned about the structure and binding region of VISTA to develop drugs that work against it and other checkpoint proteins.
"These proteins prevent our immune system from finding and destroying cancer cells," says Mehta. "So far, researchers have not had a detailed picture of what VISTA looks like on a molecular level. What we learned in this study is extremely useful when designing new drugs because it tells us which areas need to be targeted to block the function of the protein checkpoint. "
The study shows how circulating tumor cells target distant organs
Nishant Mehta et al. Structure and functional epitope of a V-domain T cell activation suppressor, Cell reports (2019). DOI: 10.1016 / j.celrep.2019.07.073
New insights into cancer-protecting protein could lead to new generation of cancer treatments (2019, 18 November)
Retrieved November 18, 2019
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