IL-12/15/18-induced cell death and mitochondrial dynamics of human NK cells

Front Immunol. 2023 Jul 27:14:1211839. doi: 10.3389/fimmu.2023.1211839. eCollection 2023.

Abstract

Natural killer (NK) cells are lymphocytes with potent antitumor functions and, consequently, several NK cell-based strategies have been developed for cancer immunotherapy. A remarkable therapeutic approach is the adoptive transfer of NK cells stimulated with IL-12, IL-15 and IL-18. This cytokine stimulation endows NK cells with properties that resemble immunological memory and, for this reason, they are known as cytokine-induced memory-like (CIML) NK cells. Very promising results have been reported in clinical trials and yet, there are still unknown aspects of CIML NK cells. Here, we have conducted a preliminary study of their mitochondrial dynamics. Our results show that upon IL-12/15/18 stimulation the viability of NK cells decreased and an increment in mitochondrial superoxide levels was observed. In addition, we found that mitochondria appeared slightly elongated and their cristae density decreased following IL-12/15/18 stimulation, possibly in a process mediated by the low levels of optic atrophy type 1 (OPA1) protein. Interestingly, although mitophagy was slightly impaired, an increase in autophagic flux was observed, which might explain the reduced viability and the accumulation of unfit mitochondria. Our findings could be of relevance in order to design new strategies intended to improve the mitochondrial fitness of IL-12/15/18-stimulated NK cells with the aim of improving their therapeutic efficacy.

Keywords: IL-12; IL-15; IL-18; NK cells; cancer immunotherapy; cytokine-preactivated NK cells; memory-like; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cytokines / metabolism
  • Humans
  • Interleukin-12
  • Interleukin-18* / pharmacology
  • Killer Cells, Natural
  • Mitochondrial Dynamics*

Substances

  • Interleukin-18
  • Cytokines
  • Interleukin-12

Grants and funding

The research in FB lab was supported by Fundacioín AECC-Spanish Association Against Cancer Foundation (PROYE16074BORR) and Health Department, Basque Government (2022333018) and BBK Fundazioa (BBK22/3196). The research in LS lab was supported by Italian Cancer Research Association (AIRC) grant IG19991. IT and AA-I are recipient of a predoctoral contract funded by the Department of Education, Basque Government (PRE_2021_2_0215 and PRE_2022_1_0063). AL-P is recipient of a predoctoral contract funded by La Caixa Foundation (100010434; LCF/BQ/DI22/11940012). GA-P is recipient of a predoctoral contract funded by Fundacioín AECC-Spanish Association Against Cancer Foundation (PRDVZ21440ASTA). GA-P and AA-I are recipient of grants from Jesuís de Gangoiti Barrera Foundation (FJGB21/001 and FJBG21/005). AS is recipient of a grant from Margarita Salas program, for the requalification of the Spanish university system 2021-2023, financed by European Union - Next Generation EU. LA is an Ikerbasque Research Fellow and FB is an Ikerbasque Research Professor, Ikerbasque, Basque Foundation for Science.