Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment.

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Stavrou, Victoria, Fultang, Livingstone ORCID: 0000-0002-8215-6660, Booth, Sarah, De Simone, Daniele, Bartnik, Arekdiusz, Scarpa, Ugo, Gneo, Luciana, Panetti, Silvia, Potluri, Sandeep, Almowaled, Meaad et al (show 13 more authors) , Barlow, Jonathan, Jankevics, Andris, Lloyd, Gavin, Southam, Andrew, Priestman, David A, Cheng, Paul, Dunn, Warwick ORCID: 0000-0001-6924-0027, Platt, Frances, Endou, Hitoshi, Craddock, Charles ORCID: 0000-0001-5041-6678, Keeshan, Karen, Mussai, Francis ORCID: 0000-0003-3342-0047 and De Santo, Carmela (2023) Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment. Cancer immunology, immunotherapy : CII, 72 (3). pp. 543-560.

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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:	Article
Uncontrolled Keywords:	Humans, Arginine, Cell Proliferation, Leukemia, Myeloid, Acute, Natural Killer T-Cells, Myeloid-Derived Suppressor Cells
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	31 Jan 2024 11:49
Last Modified:	31 Jan 2024 11:49
DOI:	10.1007/s00262-022-03268-4
Open Access URL:	https://doi.org/10.1007/s00262-022-03268-4
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3178214