Article Text

Download PDFPDF

422 Hijacking upregulated E-selectin while boosting SDF-1α sensing rewires infused NK cells to the AML-perturbed bone marrow
  1. Laura Sanz Ortega1,
  2. Agneta Andersson1 and
  3. Mattias Carlsten1,2
  1. 1Karolinska Institutet, Stockholm, Sweden
  2. 2Karolinska University Hospital, Huddinge, Sweden


Background Infusion of natural killer (NK) cells can induce anti-tumor responses in patients. Currently, most efforts to further improve the efficacy focuses on augmenting the NK cell cytotoxicity and persistence, while few addresses their tumor homing capacity, which is critical for proper tumor targeting in vivo. Indeed, increased bone marrow (BM) homing after adoptive NK cell immunotherapy has been associated with positive clinical outcome of myeloid leukemia.1 As studies have shown that tumor development in the BM can impair the homing of cytotoxic lymphocytes2,3 and that this has not yet been addressed in acute myeloid leukemia (AML), we here decipher how AML development alters the BM niche to impair NK cell infiltration and how insights can be utilized to solve this issue.

Methods Using NSG-SGM3 mice inoculated with AML cells, we assessed the microenvironmental changes in the BM during AML development using flow cytometry, immunohistochemistry, and ELISA. We genetically engineered NK cells using a clinically compliant method to equip them with selected homing molecules. Finally, we evaluated NK cell function in vitro and assessed their ability to home in vivo to different tissues in AML-bearing mice.

Results We demonstrate that NK cell BM infiltration is impaired in AML-bearing mice, closely linked to decreased levels of the CXCR4 ligand SDF-1α. Additionally, E-selectin+ endothelial cells were found increased within the BM during AML progression. Given the poor E-selectin-binding capacity of NK cells at steady-state, 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 (CXCR4R334X) rewired NK cell BM homing in AML-bearing mice nearly to the level observed in AML-free mice (figure 1).

Conclusions This work shows how impaired NK cell homing caused by AML-induced microenvironmental changes can be overcome by genetic engineering of the effector cells. We speculate that these insights can help advance future NK cell immunotherapy efforts against AML.

Acknowledgements We would like to acknowledge the Flow Cytometry Core Facility at HERM, KI, and the Animal Facility and The Unit for Morphological Phenotype Analysis at Campus Flemingsberg, KI, for excellent support. This work was supported by funding from Cancerfonden (M.C. and L.S.O.), Swedish Research Council (M.C.), Dr Åke Olssons stiftelse för forskning inom haematologi (M.C.), Barncancerfonden (M.C.), CIMED (M.C.), Felix Mindus Contribution to Leukemia Research (L.S.O) and Syskonen Svenssons Fond För Medicinsk Forskning (L.S.O).


  1. Grzywacz B, Moench L, McKenna D, Tessier KM, Bachanova V, Cooley S, Miller JS, and Courville EL. Natural Killer Cell Homing and Persistence in the Bone Marrow after Adoptive Immunotherapy Correlates with Better Leukemia Control. Journal of Immunotherapy. 2019; 42, 65–72.

  2. Ponzetta A, Benigni G, Antonangeli F, Sciumè G, Sanseviero E, Zingoni A, Ricciardi MR, Petrucci MT, Santoni A, and Bernardini G. Multiple myeloma impairs bone marrow localization of effector natural killer cells by altering the chemokine microenvironment. Cancer Res. 2015; 75, 4766–4777.

  3. van den Berk LCJ, van der Veer A, Willemse ME, Theeuwes MJGA, Luijendijk MW, Tong WH, van der Sluis IM, Pieters R, and den Boer, ML. Disturbed CXCR4/CXCL12 axis in paediatric precursor B-cell acute lymphoblastic leukaemia. Br J Haematol, 2014; 166 , 240–249.

Ethics Approval Peripheral blood cells were collected from healthy blood donor buffy coats (Ethical approval Dnr 2006/229–31/3). Animal experiments were performed under ethical approval (ID1533 and 02250–2022) by Jordbruksverket, Sweden.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.