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         headline:Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment
         description: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.
         datePublished:2022-08-13T00:00:00Z
         dateModified:2022-08-13T00:00:00Z
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            AML
            ASS
            LAT-1
            Arginine
            Cancer
            Oncology
            Immunology
            Cancer Research
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      headline:Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment
      description: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.
      datePublished:2022-08-13T00:00:00Z
      dateModified:2022-08-13T00:00:00Z
      pageStart:543
      pageEnd:560
      license:http://creativecommons.org/licenses/by/4.0/
      sameAs:https://doi.org/10.1007/s00262-022-03268-4
      keywords:
         iNKT
         AML
         ASS
         LAT-1
         Arginine
         Cancer
         Oncology
         Immunology
         Cancer Research
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      address:
         name:Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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         name:Department of Pharmacology, University of Oxford, Oxford, UK
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      address:
         name:J-Pharma Co. Ltd, Yokohama, Japan
         type:PostalAddress
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         name:Institute of Cancer and Genomics, University of Birmingham, Birmingham, UK
         type:PostalAddress
      name:University of Glasgow
      address:
         name:Paul O’Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, UK
         type:PostalAddress
      name:University of Birmingham
      address:
         name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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         name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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               name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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      name:Livingstone Fultang
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            name:University of Birmingham
            address:
               name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
               type:PostalAddress
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      name:Sarah Booth
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            name:University of Birmingham
            address:
               name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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            type:Organization
      name:Daniele De Simone
      affiliation:
            name:University of Birmingham
            address:
               name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
               type:PostalAddress
            type:Organization
      name:Arekdiusz Bartnik
      affiliation:
            name:University of Birmingham
            address:
               name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
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      name:Ugo Scarpa
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            name:University of Birmingham
            address:
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            name:University of Birmingham
            address:
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      name:Silvia Panetti
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            name:University of Birmingham
            address:
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      name:Sandeep Potluri
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            name:University of Birmingham
            address:
               name:Institute of Cancer and Genomics, University of Birmingham, Birmingham, UK
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      name:Meaad Almowaled
      affiliation:
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            address:
               name:Paul O’Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, UK
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      name:Jonathan Barlow
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            address:
               name:School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK
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            address:
               name:School of Biosciences and Phenome Centre Birmingham, University of Birmingham, Birmingham, UK
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               name:Department of Pharmacology, University of Oxford, Oxford, UK
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            address:
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            type:Organization
            name:University of Birmingham
            address:
               name:Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
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      name:Frances Platt
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            name:University of Oxford
            address:
               name:Department of Pharmacology, University of Oxford, Oxford, UK
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      name:Hitoshi Endou
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            address:
               name:J-Pharma Co. Ltd, Yokohama, Japan
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      name:Charles Craddock
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            name:University of Birmingham
            address:
               name:Institute of Cancer and Genomics, University of Birmingham, Birmingham, UK
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            type:Organization
      name:Karen Keeshan
      affiliation:
            name:University of Glasgow
            address:
               name:Paul O’Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, UK
               type:PostalAddress
            type:Organization
      name:Francis Mussai
      affiliation:
            name:University of Birmingham
            address:
               name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
               type:PostalAddress
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      email:[email protected]
      name:Carmela De Santo
      affiliation:
            name:University of Birmingham
            address:
               name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
               type:PostalAddress
            type:Organization
PostalAddress:
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
      name:Institute of Cancer and Genomics, University of Birmingham, Birmingham, UK
      name:Paul O’Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, UK
      name:School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK
      name:School of Biosciences and Phenome Centre Birmingham, University of Birmingham, Birmingham, UK
      name:School of Biosciences and Phenome Centre Birmingham, University of Birmingham, Birmingham, UK
      name:School of Biosciences and Phenome Centre Birmingham, University of Birmingham, Birmingham, UK
      name:Department of Pharmacology, University of Oxford, Oxford, UK
      name:Bio-Cancer Treatment International, Hong Kong, China
      name:Institute of Cancer and Genomics, University of Birmingham, Birmingham, UK
      name:Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
      name:Department of Pharmacology, University of Oxford, Oxford, UK
      name:J-Pharma Co. Ltd, Yokohama, Japan
      name:Institute of Cancer and Genomics, University of Birmingham, Birmingham, UK
      name:Paul O’Gorman Leukaemia Research Centre, University of Glasgow, Glasgow, UK
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
      name:Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK

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