Tetra-arsenic tetra-sulfide enhances NK-92MI mediated cellular immunotherapy in all-trans retinoic acid-resistant acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is liable to induce disseminated intravascular coagulation and has a high early mortality. Although the combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has significantly improved the complete remission rate, there are still some patients developed drug resistance. Growing evidence suggests that natural killer (NK) cell-mediated immunotherapy as a new treatment can help slow the progression of hematological malignancies. Previous studies also indicated that some tumors exhibited excellent responsiveness to NK cells in vitro. However, many clinical trial results showed that the anti-tumor effect of NK cells infusion alone was not ideal, which may be related to the inactivation of infiltrating NK cells caused by strong immunosuppression in tumor microenvironment, but the specific mechanism remains to be further explored. In the present study, we demonstrated that low doses of tetra-arsenic tetra-sulfide (As₄S₄) not only enhanced the in vitro killing of NK-92MI against ATRA-resistant APL cells, but also strengthened the growth inhibition of xenografted tumors in APL mouse model. Mechanistically, As₄S₄ altered the expression of natural killer group 2 member D ligands (NKG2DLs) and cytokines in APL cells, and PD-1 in NK-92MI cells. In addition, database retrieval results further revealed the relationship between the differentially regulated molecules of As₄S₄ and immune infiltration and its impact on prognosis. In conclusion, our findings confirmed the potential of As₄S₄ as an adjuvant for NK-92MI in the treatment of ATRA-resistant APL.