Geometric distances between immune cells key to anticancer response: study

WASHINGTON, April 30 (Xinhua) -- American researchers have discovered distances between molecules key to triggering T-cells, an essential component of the body's immune system.

A study published on Monday in the journal Nature Nanotechnology revealed the geometric underpinnings of T-cell triggering through the precise engineering of T-cell receptor geometry in all three dimensions.

They used nanofabrication used in semiconductor device processing to create a biomimetic surface that simulates the key features of the antigen-presenting cell (APC).

The immune process involves an intricate choreography of receptor proteins and their ligands at or near the surface of the T-cell and the APC.

New immunotherapies that use a patient's own T-cells to treat disease have proven strikingly effective in treating some cancers, and cancer researchers around the world are racing to improve these treatments and apply them more broadly.

"Our results could have a significant impact on the field of adoptive immunotherapy, which has been seeing remarkable success recently in treating certain cancers," said Shalom Wind, an engineering applied physicist at Columbia University.

"Our nanoengineering approach has allowed us to investigate the role that geometry plays in T-cell triggering with unprecedented precision and control," said Wind.

The biomimetic surface invented by Wind's team presented T-cell receptor ligands, molecules that bind to and stimulate receptors on the surface of the T-cell, in a variety of different geometric arrangements, with different inter-ligand spacings arranged in clusters of varying size.

They placed the ligands on "nanopedestals" on the surface, effectively controlling the distance between the T-cell and the APC, while at the same time controlling the spacing between the individual ligands.

The researchers showed that the spatial aspects of CD45, a protein whose physiological role is to inhibit T-cell receptor activation, mattered in triggering the immune response.

According to the study, if the T-cell and the APC are very close together, then CD45, which is a "big" molecule, would be "squeezed out" of the area, allowing T-cell receptor activation to proceed.

But with some additional room between the T-cells, or larger than 23 nm, CD45 can prevent the activation unless the T-cell receptor ligands are too close to one another, or below 50 nm, in which case, the lateral spacing partially squeezes out the CD45 and then the researchers observed a sharp increase in T-cell triggering.

"In our study, we were able not only to observe a spatial threshold that shows that CD45 exclusion is important, but also to see that triggering can take place even when CD45 is not entirely segregated from the T-cell receptor region, as long as the spacing is small," said Michael Dustin, a biologist professor at New York University Langone Medical Center.

With those specific knowledge of the geometric parameters underlying T-cell receptor triggering, researchers could improve some therapies by designing new chimeric antigen receptors, the basis for CAR T-cell therapy, with specific geometric features that optimize therapeutic outcomes.

"The direct evidence for a non-linear role played in and out of the plane of the membrane in T-cell receptor triggering is quite novel and has implications on the design of CAR T-cells," said Carl June, a professor of immunotherapy at the University of Pennsylvania who was not involved with the study.

"This approach might guide the development of CARs that would have better discrimination between tumor cells and normal cells that have lower densities of target," June said. Enditem