Sometimes, our T cells (shown here attacking a cancer cell) can do with a little help.
The new study — now published in the journal Cell Chemical Biology — was led by chemistry professor Amy Howell, from the University of Connecticut in Mansfield.
For years, Prof. Howell and her team sought a compound that would activate human immune cells called Invariant natural killer T (iNKT) cells.
Older studies have shown that certain compounds can activate iNKT cells in mice by stimulating the response of another type of immune cell called cytokines.
Until now, however, achieving a similar feat in human cells has eluded scientists — partly because activating iNKT cells released different types of cytokines: some stimulated an immune response, while others inhibited it.
But now, researchers have found a way around this conundrum, having designed a compound specifically so that it does not trigger a conflicting immune reaction.
The compound is called AH10-7. Prof. Howell says of it, "One of the goals in this field has been to identify compounds that elicit a more biased or selective response from iNKT cells, and we were able to incorporate features in AH10-7 that did that."
AH10-7 succeeds where others have failed
The new compound has been designed so that it selectively targets only a certain type of tumor-fighting cytokine: Th1 cytokines.
Researchers have been trying to achieve this for decades, with previous studies demonstrating that a synthetic version of so-called α-GalCer ligands — that is, ligands that regulate autoimmune responses and how our immune system responds to tumors — can fight tumors in mice.
To make an effective synthetic version of the compound for humans, Prof. Howell and her team made two main changes to it.
First of all, they added a hydrocinnamoyl ester to the sugar in the ligand, which stabilized it and boosted its ability to activate iNKT cells by holding it close to the surface of antigen molecules.
Secondly, they changed the base of the molecule, which made the compound target Th1 cytokines exclusively.
Both of these changes worked synergistically to make the compound more effective in activating human iNKT cells, explains Prof. Howell.
AH10-7 works in mice with human-like cells
Corresponding study author Jérôme Le Nours, a structural biologist at Monash University in Melbourne, Australia, explains the technology that they used to see the compound at work.
"By exposing a crystallized form of the molecular complex to a high-intensity X-ray beam at the Australian Synchrotron," Le Nours says, "we were able to obtain a detailed 3-D image of the molecular interplay between the invariant natural killer T cell receptor and AH10-7."
"This enabled us to identify the structural factors responsible for AH10-7's potency in activating iNKT cells. This valuable insight could lead to the development of even more effective anti-metastatic ligands," he adds.
Finally, the researchers also tested the compound in mice that had been genetically modified to replicate the response of human iNKT cells. AH10-7 was successful in stopping melanoma cells from growing and spreading.
Study co-author José Gascón, an associate professor of chemistry at the University of Connecticut, summarizes the findings.
"We synthesized a new compound, demonstrated its effectiveness with biological data, and learned more about its interactions with proteins through X-ray crystallography and computational analysis.''
"We are providing protocols so that other scientists can rationally design related molecules that elicit desired responses from iNKT cells," he adds.