Publication: Natural killer cell therapies

Natural killer (NK) cells are lymphocytes of the innate immune system. A key feature of NK cells is their ability to recognize a wide range of cells in distress, particularly tumour cells and cells infected with viruses. They combine both direct effector functions against their cellular targets and participate in the generation, shaping and maintenance of a multicellular immune response. As our understanding has deepened, several therapeutic strategies focused on NK cells have been conceived and are currently in various stages of development, from preclinical investigations to clinical trials. Here we explore in detail the complexity of NK cell biology in humans and highlight the role of these cells in cancer immunity. We also analyse the harnessing of NK cell immunity through immune checkpoint inhibitors, NK cell engagers, and infusions of preactivated or genetically modified, autologous or allogeneic NK cell products.

2023 heralds the fiftieth anniversary of the pioneering publications that set the stage for the discovery of NK cells 1-3 . Further characterized as a unique cellular entity distinct from other known immune cells and also officially named in 1975 4,5 , NK cells are now known to belong to the group of innate lymphoid cells (ILCs) 6 -a family of cells that has been recognized as such since 2008 7 . ILCs are lymphocytes of the innate immune system that do not express the type of diversified antigen receptors found on T cells and B cells 8 . Among the five major ILC subsets, type 1, 2 and 3 ILCs (ILC1, ILC2 and ILC3 cells, respectively) are mostly tissue-resident cells and mirror CD4 + T helper type 1 (T H 1), T H 2 and T H 17 cells, respectively, in terms of cytokine production, whereas NK cells that are present both in the blood and tissues can be considered to be innate counterparts of CD8 + cytotoxic T cells 9 . Over the past five decades, the importance and potential of NK cells has been extensively explored. What began as academic intrigue has evolved into a promising area of immunotherapy, particularly in the fight against cancer.

NK cells T cells

Natural recognition of cancer cells

Detection of stressed cells Yes Yes Multiple ligands: tumour-antigen-agnostic activity against a vast array of tumour cells Yes No (TCR mediated) Combat tumour cells with low mutation load Yes No No antigen-specific priming required Yes No No need for MHC-I expression; activity increased in absence of MHC-I expression Yes No Elimination of cancer cells Direct killing of tumour cells Yes Yes Production of cytokines and chemokines that shape T cell responses Yes Yes Activity against primary tumours and metastasis Yes Yes Clinical studies have demonstrated Efficacy in haematological malignancies Yes Yes Excellent safety profile of cell infusions Yes No (graft-versus-host disease)