New research has identified the mechanisms responsible for enhancing immune system activity, offering new approaches for more effective cancer treatments and vaccines.
Invariant natural killer T (iNKT) cells are part of the immune system’s arsenal for fighting infection and defeating diseases like cancer. Finding ways to activate these potent cells more quickly could lead to more effective solutions to cancer and other diseases.
Finding an effective way to activate iNKT Cells
While there have been efforts to find compounds that stimulate iNKT cells, and a number of compounds have been demonstrated to do so in mice, the results so far in human cells have been poor.
However, that may be set to change after a new study published in Cell Chemical Biology . This study, conducted by an international team of researchers led by chemistry professor Amy Howell from the University of Connecticut, involved a new compound that appears to do exactly what is needed.
The compound, known as AH10-7, is a modified version of a previously synthesized ligand and appears to be able to both robustly activate human iNKT cells and selectively stimulate these cells so that they release anti-tumor signals called Th1 cytokines.
This is an improvement over previous compounds, which normally caused human iNKT cells to release a range of cytokines, some of which had conflicting functions. These contradictory signals disrupted the desired activation of the iNKT cells, hampering the immune response.
Computational molecular analysis guides intelligent drug design
AH10-7 is designed to avoid generating conflicting signals during activation, as it causes a selective response from the iNKT cells. Aided by advanced 3D computer modeling, the researchers spent years developing this compound and ensuring that it works properly. This modeling allowed the researchers to understand what was happening at a molecular level and represents a new approach for designing better drugs.
The team learned about how AH10-7 worked and its interactions with proteins by using X-ray crystallography and computational molecular analysis. The researchers exposed a crystallized form of the molecular complex to a high-intensity X-ray beam and were able to obtain a detailed 3D image that mapped the molecular interactions between the iNKT cell receptors and the AH10-7 compound. This allowed them to work out the exact reason why AH10-7 is effective in activating iNKT cells.
The team is now making its protocols available to other researchers, allowing them to design similar molecules that can provoke selective and desired responses from iNKT cells.
Researchers have been trying to harness the potential of human iNKT cells for almost twenty years ever since the discovery that certain natural and synthetic glycolipid ligands known as alpha-galactosylceramides (α-GalCers) could activate iNKT cells. These α-GalCers function as regulators in our immune system, assisting antigen-presenting cells to attract and bind with iNKT cells in order to become activated and ready to fight invading pathogens or combat cancer.
During the study, the team modified an α-GalCer in two important ways to bolster its effectiveness. The team discovered that adding a hydrocinnamoyl ester onto the sugar helped to stabilize the ligand, keeping it close to the surface of the antigen-presenting cell, thus making it easier to dock with the iNKT cell and activate it. The team also removed part of the molecule’s sphingoid base, which appears to encourage it to favor the production of Th1 when activating iNKT cells.
To test the effectiveness of AH10-7, the research team tested the compound in wild-type and transgenic mice that had been genetically engineered to mimic the human iNKT cell response.
AH10-7 proved to be equally effective to a similar compound called KRN7000 in suppressing the growth of melanoma in the transgenic mice. KRN7000 was a previously synthesized α-GalCer that robustly stimulated iNKT cells in mice and humans; however, it also activated a variety of cytokines, many of which had conflicting or undesirable side effects. In fact, it was this lack of specificity that led to the search for better compounds, including AH10-7, that are much more specific in the activation of Th1 cytokines.
The results here are promising, and being able to harness the power of iNKT cells reliably is a great step forward for immunotherapy and the fight against cancer and other age-related diseases.
 Chennamadhavuni, D., Saavedra-Avila, N. A., Carreño, L. J., Guberman-Pfeffer, M. J., Arora, P., Yongqing, T., … & Sundararaj, S. (2018). Dual Modifications of α-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity. Cell Chemical Biology.