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

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...

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Published inCell metabolism Vol. 33; no. 6; pp. 1205 - 1220.e5
Main Authors Poznanski, Sophie M., Singh, Kanwaldeep, Ritchie, Tyrah M., Aguiar, Jennifer A., Fan, Isabella Y., Portillo, Ana L., Rojas, Eduardo A., Vahedi, Fatemeh, El-Sayes, Abdullah, Xing, Sansi, Butcher, Martin, Lu, Yu, Doxey, Andrew C., Schertzer, Jonathan D., Hirte, Hal W., Ashkar, Ali A.
Format Journal Article
LanguageEnglish
Published United States 01.06.2021
Subjects
Adult
Aged
Animals
Antineoplastic Agents - immunology
Cell Line, Tumor
Female
Humans
Immunotherapy - methods
Killer Cells, Natural - cytology
Killer Cells, Natural - immunology
Male
Mice
Middle Aged
Neoplasms - therapy
Tumor Microenvironment
Young Adult
NK cells
metabolic flexibility
immunometabolism
cancer immunotherapy
NK cell metabolism
tumor microenvironment
adoptive cell therapy
glucose metabolism
oxidative stress
Warburg effect
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Summary: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.
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ISSN:1550-4131
1932-7420
1932-7420
DOI:10.1016/j.cmet.2021.03.023