AI Article Synopsis
- Researchers are exploring ways to boost the antitumor activity of natural killer (NK) cells using interleukin-15 (IL-15), but concerns exist regarding potential toxicity and the risk of promoting cancers or autoimmune diseases.
- A new platform called IL15RB has been developed, allowing IL-15 to be tethered to its receptor, leading to indefinite NK92 cell expansion without the need for additional cytokines.
- Results indicate that NK92 cells expressing IL15RB show enhanced anticancer effects and resistance to certain treatments, though exposure to TGFβ1 diminishes their killing ability, highlighting the importance of addressing this in immunotherapy strategies.
Article Abstract
Background: Enhancing NK cells' antitumor activity requires sustained cytokine signaling. Interleukin-15 (IL-15) is a potent immunostimulatory cytokine used to armor CAR-NK and CAR-T cell immunotherapies. However, strategies to increase IL-15 expression and antitumor effect may trigger systemic toxicity with the potential to promote oncogenesis and autoimmune diseases.
Methods: To overcome these limitations, we developed a new platform (IL15RB) whereby IL-15 with IL-2 signal peptide is tethered to its receptor, IL2Rβ.
Results: NK92-expressing IL15RB (NK92) cells expand indefinitely without exogenous cytokines and have significantly higher anticancer activity than NK-92 stimulated by IL-15, IL-2, or expressing tethered IL-2. NK92 showed resistance to irradiation and IL-4. However, TGFβ1 substantially reduced NK92 killing, suggesting the need to inhibit TGFβ1 in IL-15-mediated immunotherapies. IL15RB induced strong STAT3 but weaker STAT5 and STAT1 activation compared to IL-2. Chronic exposure of NK92 cells to cancer cells reduced STAT3 and STAT1 activation irreversibly, suggesting a role in exhaustion. Combination with CAR-CD19 enhanced NK92 antitumor activity against leukemia and increased its STAT5 activation. NK92 anti-tumors activity was further enhanced by combination with anti-PD1.
Conclusion: Our data suggest that the tethering of IL-15 to its receptor IL2Rβ empowers NK cell cytolytic activity. Additionally, the tethering of IL-15 will prevent any systemic risk of toxicity.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472742 | PMC |
| http://dx.doi.org/10.2147/ITT.S490498 | DOI Listing |
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