Artificial Molecule Shown to Stimulate NKT Cells in Mice
Natural killer T-cells, or NKT Cells, are a secondary type of T-cell that search the body for stressed and abnormal cells, playing significant regulatory roles in numerous immune responses, including anti-tumor responses.
These cells can attack cancer cells directly or through the recruitment and activation of other immune cells. The immune responses of NKT cells are initiated through foreign fat molecules recognition.
Well-known for fast production of large amounts of cytokines, NKT cells signal molecules that are essential for communication between cells of the immune system. They can produce regulatory, pro-inflammatory, and anti-inflammatory cytokines.
Prior studies have shown that the foreign fat molecule alpha-galactosylceramide (α-GalCer) could be a potential cell-targeted immunotherapy to treat cancer because it is a powerful stimulator of NKT cells with anti-cancer responses.
It has also been found that artificial α-GalCer, or deviations of the molecule, stimulate anti-cancer immune responses via NKT cells in mouse models. However, these compounds have shown limited effects in human cancer patients.
Researchers think that the reason behind these disappointing results in humans are due to current compounds stimulating NKT cells to produce different types of cytokines with conflicting effects, like pro- and anti-inflammatory cytokines — leading to ineffective and unpredictable immune responses.
Scientists have now developed AH10-7, a new version of the artificial compound that induces the production of a specific set of pro-inflammatory cytokines — known as Th1 cytokines — which stimulate anti-tumor immune responses.
A study called “Dual Modifications of a-Galactosylceramide Synergize to Promote Activation of Human Invariant Natural Killer T Cells and Stimulate Anti-tumor Immunity,” was published in the journal Cell Chemical Biology.
Along with the technology used in the study, these findings may help develop more effective treatments that could stop cancer from spreading.
To attain this, researchers performed two chemical alterations in an α-GalCer molecule, which boosted the stability of the molecule — improving its recognition by NKT cells — and induced a specific anti-tumor response.
Examinations commenced to test the effectiveness of AH10-7 in mice with melanoma, along with a “humanized” mouse model, which had been genetically altered to imitate the response of human NKT cells.
The team wrote that “the pairing of structural modifications used in the design of this compound may be a promising path for development of human therapeutics,” after finding out that AH10-7 can effectively suppress melanoma cell growth and spread, both in normal and “humanized” mice.
To better understand the effects at the molecular level, the researchers used advanced structural and 3D computer modeling analysis of the two chemical modifications present in AH10-7. This approach could potentially support the development of new and even more effective NKT cell-activator compounds.