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New insights into a cancer-protecting protein can guide a new generation of cancer treatments



  New insight on a cancer-protecting protein could guide a new generation of cancer treatments
Using a combination of calculation and experimentation, researchers were able to map the shape of VISTA, a "checkpoint" protein that defends cancer cells from immune system attacks, as well as that part of the protein molecule that the immune system can recognize and target. Credit: SLAC National Accelerator Laboratory

In a paper published in Cell Reports a research group 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 immune system strikes . A better understanding of how this protein works can guide the design of treatments targeting these proteins and infiltrate cancer's first line of defense.

Picking the weeds

The human body consists of trillions of cells that are constantly created, destroyed and replaced with new ones, like grass blades 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 straightforward. 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 cover themselves, using special "checkpoint" proteins such as VISTA, and masked as 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 has been shown to act as an invisibility cover of sorts to protect a tumor from recognition and destruction of the immune system. " a remarkable force in the treatment of various cancers because they allow the immune system to find and destroy cancer cells without the toxic effects of chemotherapy, but due to a lack of information on how checkpoint proteins work, these drugs are effective for only about a quarter of patients. [1

9659006] In a first team, Cochran led , 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 its 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.

Breakdown of Defense

To follow up this research, Mehta hopes to use what they learned about the structure and bond region of VISTA to develop drugs that counteract it and other checkpoints.

"These proteins prevent our immune systems from finding and destroying cancer cells," Mehta says. "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."


Study shows how circulating tumor cells target distant organs


More information:
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

Provided by
SLAC National Accelerator Laboratory




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New insights on a cancer-protecting protein can guide a new generation of cancer treatments (2019, November 18)
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