Human NK cells and cancer

Oncoimmunology. 2024 Jul 16;13(1):2378520. doi: 10.1080/2162402X.2024.2378520. eCollection 2024.

Abstract

The long story of NK cells started about 50 y ago with the first demonstration of a natural cytotoxic activity within an undefined subset of circulating leukocytes, has involved an ever-growing number of researchers, fascinated by the apparently easy-to-reach aim of getting a "universal anti-tumor immune tool". In fact, in spite of the impressive progress obtained in the first decades, these cells proved far more complex than expected and, paradoxically, the accumulating findings have continuously moved forward the attainment of a complete control of their function for immunotherapy. The refined studies of these latter years have indicated that NK cells can epigenetically calibrate their functional potential, in response to specific environmental contexts, giving rise to extraordinarily variegated subpopulations, comprehensive of memory-like cells, tissue-resident cells, or cells in various differentiation stages, or distinct functional states. In addition, NK cells can adapt their activity in response to a complex body of signals, spanning from the interaction with either suppressive or stimulating cells (myeloid-derived suppressor cells or dendritic cells, respectively) to the engagement of various receptors (specific for immune checkpoints, cytokines, tumor/viral ligands, or mediating antibody-dependent cell-mediated cytotoxicity). According to this picture, the idea of an easy and generalized exploitation of NK cells is changing, and the way is opening toward new carefully designed, combined and personalized therapeutic strategies, also based on the use of genetically modified NK cells and stimuli capable of strengthening and redirecting their effector functions against cancer.

Keywords: Human natural killer cells; NK cell receptors; NK cell-based immunotherapy; receptor–ligand interactions; tumor escape; tumor microenvironment.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Immunotherapy / methods
  • Killer Cells, Natural* / immunology
  • Neoplasms* / immunology
  • Neoplasms* / pathology
  • Neoplasms* / therapy

Grants and funding

Supported by the following grants: Fondazione AIRC [AIRC 5 × 10002018 id. 21147 to L.M. and S.S.; AIRC IG id. 25023 to MV]; Italian Ministry of Health Ricerca Finalizzata [RF-2018-12366714 to MV]; Italian Ministry of Health 5 × 1000 - 2018 and Ricerca Corrente provided by IRCCS Ospedale Policlinico San Martino to M.V., G.P., and D.P.; Ricerca Corrente provided by IRCCS Istituto Giannina Gaslini to C.C and M.F.