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

Poznanski Sophie M.; Singh Kanwaldeep; Ritchie Tyrah M.Aguiar Jennifer A.Fan Isabella Y.Portillo Ana L.Rojas Eduardo A.Vahedi FatemehEl-Sayes AbdullahXing SansiButcher MartinLu YuDoxey Andrew C.Schertzer Jonathan D.Hirte Hal W.Ashkar Ali A.

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

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

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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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《Cell metabolism》 |2021年第6期|1205-1220|共21页
作者
Poznanski Sophie M.; Singh Kanwaldeep; Ritchie Tyrah M.Aguiar Jennifer A.Fan Isabella Y.Portillo Ana L.Rojas Eduardo A.Vahedi FatemehEl-Sayes AbdullahXing SansiButcher MartinLu YuDoxey Andrew C.Schertzer Jonathan D.Hirte Hal W.Ashkar Ali A.;
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McMaster Univ, McMaster Immunol Res Ctr, Dept Med, Hamilton, ON L8N 3Z5, Canada;

McMaster Univ, Dept Oncol, Hamilton, ON L8V 5C2, Canada;

Juravinski Canc Ctr, Hamilton, ON L8V 5C2, CanadaMcMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8S 4K1, CanadaUniv Waterloo, Dept Biol, Waterloo, ON N2L 3G1, Canada;

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中图分类内分泌腺疾病及代谢病;
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Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment

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