Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment

Victoria Stavrou, Livingstone Fultang, Sarah Booth, Daniele De Simone, Arekdiusz Bartnik, Ugo Scarpa, Luciana Gneo, Silvia Panetti, Sandeep Potluri, Meaad Almowaled, Jonathan Barlow, Andris Jankevics, Gavin Lloyd, Andrew Southam, David A. Priestman, Paul Cheng, Warwick Dunn, Frances Platt, Hitoshi Endou, Charles CraddockKaren Keeshan, Francis Mussai*, Carmela De Santo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.
Original languageEnglish
Number of pages18
JournalCancer Immunology Immunotherapy
Early online date13 Aug 2022
DOIs
Publication statusE-pub ahead of print - 13 Aug 2022

Bibliographical note

Funding 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].

Funding Information:
The authors thank the patients and parents who contributed samples to the study. Thank you to Jane Cooper, Cay Shakespeare, and Sarah-Jane Staveley for consenting of patients and collection of samples for this study. 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].

Publisher Copyright:
© 2022, The Author(s).

Keywords

  • iNKT
  • AML
  • ASS
  • LAT-1
  • Arginine
  • Cancer

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