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Measurement of Natural Killer Cell-Mediated Cytotoxicity and Migration in the Context of Hepatic Tumor Cells
Published on: February 22, 2020
SLC1A1 mediated glutamine addiction and contributed to natural killer T-cell lymphoma progression with
Jie Xiong1, Nan Wang1, Hui-Juan Zhong1
1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine, Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background:
Metabolic reprogramming plays an essential role on lymphoma progression. Dysregulation of glutamine metabolism is implicated in natural-killer T-cell lymphoma (NKTCL) and tumor cell response to asparaginase-based anti-metabolic treatment.
Methods:
To understand the metabolomic alterations and determine the potential therapeutic target of asparaginase, we assessed metabolomic profile using liquid chromatography-mass spectrometry in serum samples of 36 NKTCL patients, and integrated targeted metabolic analysis and RNA sequencing in tumor samples of 102 NKTCL patients. The biological function of solute carrier family 1 member 1 (SLC1A1) on metabolic flux, lymphoma cell growth, and drug sensitivity was further examined in vitro in NK-lymphoma cell line NK-92 and SNK-6, and in vivo in zebrafish xenograft models.
Findings:
In NKTCL patients, serum metabolomic profile was characterized by aberrant glutamine metabolism and SLC1A1 was identified as a central regulator of altered glutaminolysis. Both in vitro and in vivo, ectopic expression of SLC1A1 increased cellular glutamine uptake, enhanced glutathione metabolic flux, and induced glutamine addiction, leading to acceleration of cell proliferation and tumor growth. Of note, SLC1A1 overexpression was significantly associated with PD-L1 downregulation and reduced cytotoxic CD3+/CD8+ T cell activity when co-cultured with peripheral blood mononuclear cells. Asparaginase treatment counteracted SLC1A1-mediated glutamine addiction, restored SLC1A1-induced impaired T-cell immunity. Clinically, high EAAT3 (SLC1A1-encoded protein) expression independently predicted superior progression-free and overall survival in 90 NKTCL patients treated with asparaginase-based regimens.
Interpretation:
SLC1A1 functioned as an extracellular glutamine transporter, promoted tumor growth through reprogramming glutamine metabolism of NKTCL, while rendered tumor cells sensitive to asparaginase treatment. Moreover, SLC1A1-mediated modulation of PD-L1 expression might provide clinical rationale of co-targeting metabolic vulnerability and immunosuppressive microenvironment in NKTCL.
Funding:
This study was supported, in part, by research funding from the National Natural Science Foundation of China (82130004, 81830007 and 81900192), Chang Jiang Scholars Program, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support (20152206 and 20152208), Clinical Research Plan of SHDC (2020CR1032B), Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine (DLY201601), Shanghai Chenguang Program (19CG15), Shanghai Sailing Program (19YF1430800), Medical-Engineering Cross Foundation of Shanghai Jiao Tong University (ZH2018QNA46), and Shanghai Yi Yuan Xin Xing Program.
Insights
Solute carrier family 1 member 1 (SLC1A1) drives natural-killer T-cell lymphoma (NKTCL) growth by altering glutamine metabolism. Targeting SLC1A1 enhances sensitivity to asparaginase treatment and may improve T-cell immunity in NKTCL patients.
Area of Science:
- Oncology
- Metabolic pathways
- Immunotherapy
Background:
- Metabolic reprogramming is crucial in lymphoma progression.
- Glutamine metabolism dysregulation is observed in natural-killer T-cell lymphoma (NKTCL).
- Altered glutamine metabolism impacts tumor response to asparaginase treatment.
Purpose of the Study:
- To investigate metabolomic alterations in NKTCL.
- To identify potential therapeutic targets for asparaginase treatment.
- To elucidate the role of solute carrier family 1 member 1 (SLC1A1) in NKTCL.
Main Methods:
- Serum metabolomic profiling using liquid chromatography-mass spectrometry in 36 NKTCL patients.
- Integrated targeted metabolic analysis and RNA sequencing in tumor samples from 102 NKTCL patients.
- In vitro and in vivo functional studies of SLC1A1 in NK-lymphoma cell lines and zebrafish xenograft models.
Main Results:
- Aberrant glutamine metabolism and SLC1A1 as a central regulator of glutaminolysis were identified in NKTCL patients.
- Ectopic SLC1A1 expression increased glutamine uptake, enhanced glutathione metabolism, and promoted cell proliferation and tumor growth.
- SLC1A1 overexpression correlated with PD-L1 downregulation and reduced cytotoxic T-cell activity, but asparaginase treatment reversed these effects.
Conclusions:
- SLC1A1 promotes NKTCL growth by reprogramming glutamine metabolism and confers sensitivity to asparaginase.
- SLC1A1-mediated modulation of PD-L1 suggests potential for co-targeting metabolic vulnerabilities and the immunosuppressive tumor microenvironment.
- High EAAT3 (SLC1A1) expression predicts better survival in NKTCL patients treated with asparaginase-based regimens.
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