Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment

Stavrou, V. et al. (2023) Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment. Cancer Immunology, Immunotherapy, 72(3), pp. 543-560. (doi: 10.1007/s00262-022-03268-4) (PMID:35962843) (PMCID:PMC9947083)

Abstract

Acute myeloid leukaemia (AML) creates an immunosuppressive environment to conventional T cells through Arginase 2 (ARG2)-induced arginine depletion. We identify that AML blasts release the acute phase protein serum amyloid A (SAA), which acts in an autocrine manner to upregulate ARG2 expression and activity, and promote AML blast viability. Following in vitro cross-talk invariant natural killer T (iNKT) cells become activated, upregulate mitochondrial capacity, and release IFN-γ. iNKT retain their ability to proliferate and be activated despite the low arginine AML environment, due to the upregulation of Large Neutral Amino Acid Transporter-1 (LAT-1) and Argininosuccinate Synthetase 1 (ASS)-dependent amino acid pathways, resulting in AML cell death. T cell proliferation is restored in vitro and in vivo. The capacity of iNKT cells to restore antigen-specific T cell immunity was similarly demonstrated against myeloid-derived suppressor cells (MDSCs) in wild-type and Jα18−/− syngeneic lymphoma-bearing models in vivo. Thus, stimulation of iNKT cell activity has the potential as an immunotherapy against AML or as an adjunct to boost antigen-specific T cell immunotherapies in haematological or solid cancers.

• Item Type: Articles
• Additional Information: This work was supported by Cancer Research UK, the Little Princess Trust, Treating Children with Cancer, Amber Phillpott Trust, Birmingham Children’s Hospital Research Fund/ Carter the Brave, and the alumni and donors to the University of Birmingham. This work was supported by Phenome Centre Birmingham [MR/M009157/1].
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Almowaled, Meaad Saeed J and Keeshan, Dr Karen
• Authors: Stavrou, V., Fultang, L., Booth, S., De Simone, D., Bartnik, A., Scarpa, U., Gneo, L., Panetti, S., Potluri, S., Almowaled, M., Barlow, J., Jankevics, A., Lloyd, G., Southam, A., Priestman, D. A., Cheng, P., Dunn, W., Platt, F., Endou, H., Craddock, C., Keeshan, K., Mussai, F., and De Santo, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cancer Immunology, Immunotherapy
• Publisher: Springer
• ISSN: 0340-7004
• ISSN (Online): 1432-0851
• Published Online: 13 August 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Cancer Immunology, Immunotherapy 72(3): 543-560
• Publisher Policy: Reproduced under a Creative Commons license