2. Academic Validation
  3. Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment

Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment

  • Cell Metab. 2021 Jun 1;33(6):1205-1220.e5. doi: 10.1016/j.cmet.2021.03.023.
Sophie M Poznanski 1,  Kanwaldeep Singh 2,  Tyrah M Ritchie 1,  Jennifer A Aguiar 3,  Isabella Y Fan 1,  Ana L Portillo 1,  Eduardo A Rojas 1,  Fatemeh Vahedi 1,  Abdullah El-Sayes 1,  Sansi Xing 4,  Martin Butcher 5,  Yu Lu 4,  Andrew C Doxey 3,  Jonathan D Schertzer 6,  Hal W Hirte 7,  Ali A Ashkar 8
Affiliations

Affiliations

  • 1 Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada.
  • 2 Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada.
  • 3 Department of Biology, University of Waterloo, Waterloo, ON N2L 3G1, Canada.
  • 4 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
  • 5 Juravinski Cancer Centre & McMaster University, Hamilton, ON L8V 5C2, Canada.
  • 6 Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada; Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, ON L8S 4K1, Canada.
  • 7 Department of Oncology, McMaster University, Hamilton, ON L8V 5C2, Canada; Division of Medical Oncology, Juravinski Cancer Centre, Hamilton, ON L8V 5C2, Canada.
  • 8 Department of Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8N 3Z5, Canada. Electronic address: ashkara@mcmaster.ca.
PMID: 33852875 DOI: 10.1016/j.cmet.2021.03.023
Abstract

NK cells are central to anti-tumor immunity and recently showed efficacy for treating hematologic malignancies. However, their dysfunction in the hostile tumor microenvironment remains a pivotal barrier for Cancer immunotherapies against solid tumors. Using Cancer patient samples and proteomics, we found that human NK cell dysfunction in the tumor microenvironment is due to suppression of glucose metabolism via lipid peroxidation-associated oxidative stress. Activation of the Nrf2 antioxidant pathway restored NK cell metabolism and function and resulted in greater anti-tumor activity in vivo. Strikingly, expanded NK cells reprogrammed with complete metabolic substrate flexibility not only sustained metabolic fitness but paradoxically augmented their tumor killing in the tumor microenvironment and in response to nutrient deprivation. Our results uncover that metabolic flexibility enables a cytotoxic immune cell to exploit the metabolic hostility of tumors for their advantage, addressing a critical hurdle for Cancer Immunotherapy.

Keywords

NK cell metabolism; NK cells; Warburg effect; adoptive cell therapy; cancer immunotherapy; glucose metabolism; immunometabolism; metabolic flexibility; oxidative stress; tumor microenvironment.

Figures
Products