利用上调的 E-selectin 并增强 SDF-1α感知，重定向输注的 NK 细胞至 AML 扰动的骨髓

Increased bone marrow (BM) homing of NK cells is associated with positive outcome in patients with acute myeloid leukemia (AML) treated within adoptive NK cell transfer trials. While most efforts to further improve the efficacy focus on augmenting NK cell persistence and cytotoxicity, few address their ability to home to the tumor.

Here, we decipher how AML growth alters the BM niche to impair NK cell infiltration and how insights can be utilized to resolve this issue.

We show that AML development gradually impairs the BM homing capacity of infused NK cells, which was tightly linked to loss of SDF-1α in this environment. AML development also triggered up-regulation of E-selectin on BM endothelial cells. Given the poor E-selectin-binding capacity of NK cells, introduction of fucosyltransferase-7 (FUT7) to the NK cells per mRNA transfection resulted in potent E-selectin binding and stronger adhesion to E-selectin + endothelial cells.

Co-introduction of FUT7 and gain-of-function CXCR4 (CXCR4 R334X ) redirected NK cell homing to the BM of AML-bearing mice nearly to the levels in AML-free mice. This work shows how impaired NK cell homing caused by AML-induced microenvironmental changes can be overcome by genetic engineering.

We speculate our insights can help further advance future NK cell immunotherapies.