DNA damage agents trigger iNKT cell-mediated elimination of AML cells through activation of NF-κB/HLA-DRB6/CD1d pathway.

Acute myeloid leukemia (AML) is the most common and deadly type of leukemia with the high recurrence rates and poor prognosis. Despite extensive exploration of therapeutic strategies, there is currently no effective remedy for AML. Recently, there has been a growing focus on immunotherapeutic approaches for treating hematologic malignancies. CD1d-restricted invariant Natural Killer T (iNKT) cells have been recognized for their significant role in antitumor immunity. This study identified a potential therapeutic strategy based on the iNKT cells and demonstrated that treating AML cells with DNA damage agents can enhance iNKT cell-mediated cytotoxicity in vitro. Research has also demonstrated that DNA damage regulates CD1d gene transcription activity by specifically activating NF-κB/RELA. Additionally, lncRNA-HLA-DRB6 is involved in the targeted regulation of CD1d by RELA, thus promoting the stability of CD1d mRNA in the cytoplasm. The activation of the RELA/lncRNA-HLA-DRB6/CD1d pathway by DNA damage contributes to sensitizing AML cells to killing by iNKT cells. Furthermore, combination treatment with α-galactosylceramide (α-GalCer; which is an activator of iNKT cells) and DNA damage agents exhibited synergistic antitumor effects in vivo, which may be beneficial for alleviating the progression of AML. In conclusion, these findings provide information on the mechanism by which DNA damage in AML cells regulates iNKT cell activity, thus suggesting that the development of immune therapeutic strategies based on iNKT cells during chemotherapy may represent a potential avenue for AML treatment.