Natural Killer Cells as an Immune Cell Therapy Option for Bone Marrow Transplantation in Hematological Malignancies: Implications for New Therapies Based on Lipid Transfer and Cell-to- Cell Communication

Natural killer (NK) cells belong to the innate immune system. In recent years it has been suggested that their use could improve the outcome of stem cell transplantation for hematological malignancies, mainly due to the high anti-tumor effect they mediate and because they are not associated with an increase of the graft versus host disease, a complication which decreases the survival of patients submitted to this procedure. Once activated by several mechanisms, NK cells deliver cytolytic molecules triggering different cell death pathways, which can be caspase-3 dependent or caspase-3 independent, such as endoplasmic reticulum stress or lysosomal cell death. Apparently, NK cells take advantage of the particular features of different tumor cells to attack them in a more efficient way. Understanding the factors that contribute to cancer cell death is therefore critical for the development of novel therapies and to circumvent chemo-resistance.

Lipids are emerging as new targets for anti-inflammatory and cancer therapies as they interact extensively with organelles, are involved in immune responses, and can lead to initiation of different types of cell death. Interactions between lipids with membranes are crucial for the effects they mediate in cell-to-cell communication. Our group demonstrated that cord blood derived NK cells (CB-NK) can be efficiently expanded in vitro and exert anti-tumor activity both in vitro and in vivo in a multiple myeloma (MM) model thus, providing a clinically applicable strategy for the generation of highly functional NK cells which can be used to eradicate this and potentially other hematological malignancies. Our group also showed that CB-NK mediate a specific tumor cell death against MM which is transmissible between cells, and where lipidprotein vesicle trafficking play a relevant role. These findings provide the rationale for the development of CB-NK based therapeutic strategies in the treatment of hematological malignancies.

In this paper, the strengths and the weaknesses of clinical trials using NK cells are discussed. In addition, some guidelines for the development of future trials are suggested.

Keywords: Stem cell transplantation (SCT), natural killer (NK) cells, cell death, lipids, cell-to-cell communication, autophagy, multiple myeloma (MM).