Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment

• Published in: Cancer Immunology, Immunotherapy Vol. 72; no. 3; pp. 543 - 560
• Main Authors: Stavrou, Victoria, Fultang, Livingstone, Booth, Sarah, De Simone, Daniele, Bartnik, Arekdiusz, Scarpa, Ugo, Gneo, Luciana, Panetti, Silvia, Potluri, Sandeep, Almowaled, Meaad, Barlow, Jonathan, Jankevics, Andris, Lloyd, Gavin, Southam, Andrew, Priestman, David A., Cheng, Paul, Dunn, Warwick, Platt, Frances, Endou, Hitoshi, Craddock, Charles, Keeshan, Karen, Mussai, Francis, De Santo, Carmela
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2023; Springer Nature B.V
• Subjects: Acute myeloid leukemia; Acute phase proteins; Amino acids; Amyloid; Antigens; Arginase; Arginine; Autocrine signalling; Cancer Research; Cell death; Cell Proliferation; Humans; Immunology; Immunotherapy; Leukemia; Leukemia, Myeloid, Acute; Lymphocytes; Lymphocytes T; Lymphoma; Medicine; Medicine & Public Health; Mitochondria; Myeloid-Derived Suppressor Cells; Natural killer cells; Natural Killer T-Cells; Oncology; Original; Original Article; Suppressor cells; γ-Interferon; AML; ASS; Arginine; iNKT; LAT-1; Cancer
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-022-03268-4

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.