In an article published in cell Reports, a team of researchers from the Department of Energy's SLAC National Accelerator Laboratory and Stanford University discovered unique properties of a protein called VISTA that protects cancer cells against strikes from the immune system. A better understanding of how this protein works can guide the design of treatments that target these proteins and infiltrate cancer's first line of defense.
Pick the weeds
The human body is made up of trillions of cells that are constantly created, destroyed and replaced with new ones, such as turf on a lawn. But when cells begin to grow and divide uncontrollably, like irritating weeds, they can form a solid mass called a tumor. If cancer, this tumor can deepen its roots and spread to other parts of the body.
The solution seems simple. Just like weeding a garden, the immune system can attack these diseased cells and soothe cancer in the bud. But the tumors have a secret weapon: the ability to cut themselves using special "checkpoint" proteins like VISTA and masked like normal, fresh grass.
"When tumor cells arise, they are recognized as foreign and purified by the immune system through specialized cells called T cells," said Jennifer Cochran, a professor of bioengineering at Stanford University. "But surface markers on the cells surrounding the tumor, known as" immune checkpoints ", have been shown to act as an invisibility cover of sorts to protect a tumor from immune system recognition and destruction."
Stripping the invisibility cloak
FDA-approved antibodies that erase this coat of invisibility and release immune system attacks against tumors have shown remarkable power in the treatment of various cancers because they allow the immune system to find and destroy cancer cells without the toxic effects of chemotherapy. However, due to a lack of information on how protein checkpoints work, these drugs are only effective for about a quarter of patients.
In a first management led by Cochran, Possu Huang, professor of bioengineering at Stanford, and Nishant Mehta, a Stanford Ph.D. candidate, in collaboration with Irimpan Mathews, a researcher at Stanford Synchrotron Radiation Lightsource (SSRL), was able to map the structure of VISTA at high resolution, which required a combination of calculation and experimental techniques.
To better understand the structure, the researchers crystallized VISTA molecules and then measured how the crystals blast X-rays at one of SSRL's specialized beam lines. When researchers analyzed data using computational tools, the patterns formed when the X-rays irradiated the crystals allowed them to map the protein's shape and detailed atomic structure 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 the collaboration of experts in molecular engineering, protein design and structural biology," says Mathews.
To break down defense
To follow up this research, Mehta hopes to use what they learned about the structure and bonding region of VISTA to develop drugs that counteract it and other checkpoints.
"These proteins prevent our immune systems from finding and destroying cancer cells," says Mehta. "Until now, researchers did not have a detailed picture of what VISTA looks like at the molecular level. What we learned in this study is extremely useful for designing new drugs because it tells us which areas to target to block the control point's protein."
The study shows how circulating tumor cells target distant organs
Nishant Mehta et al. Structure and functional binding epitope of V-domain Ig suppressor of T-cell activation, cell Reports (2019). DOI: 10.1016 / j.celrep.2019.07.073
New insights into a cancer-protecting protein can guide a new generation of cancer treatments (2019, November 18)
Retrieved November 18, 2019
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