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 Craddock; Karen Keeshan; Francis Mussai; Carmela De Santo

doi:10.1007/s00262-022-03268-4

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 journal › Article › peer-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 language	English
Number of pages	18
Journal	Cancer Immunology Immunotherapy
Early online date	13 Aug 2022
DOIs	https://doi.org/10.1007/s00262-022-03268-4
Publication status	E-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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10.1007/s00262-022-03268-4Licence: Creative Commons: Attribution (CC BY)

StavrouV2022InvariantFinal published version, 2.75 MBLicence: Creative Commons: Attribution (CC BY)

Integrating innovative technologies for genotyping in stratified medicine
Moss, P. (Co-Investigator), Dunn, W. (Co-Investigator), Beggs, A. (Co-Investigator), Viant, M. (Co-Investigator), Drayson, M. (Co-Investigator), Adams, D. (Principal Investigator), Bonifer, C. (Co-Investigator) & Guenther, U. (Co-Investigator)
Medical Research Council
1/04/15 → 1/07/18
Project: Research Councils

Cite this

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., ... De Santo, C. (2022). Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment. Cancer Immunology Immunotherapy. Advance online publication. https://doi.org/10.1007/s00262-022-03268-4

@article{e552310cdda24b059be7b94105d7761e,

title = "Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment",

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.",

keywords = "iNKT, AML, ASS, LAT-1, Arginine, Cancer",

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

note = "Funding Information: This work was supported by Cancer Research UK, the Little Princess Trust, Treating Children with Cancer, Amber Phillpott Trust, Birmingham Children{\textquoteright}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{\textquoteright}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: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = aug,

day = "13",

doi = "10.1007/s00262-022-03268-4",

language = "English",

journal = "Cancer Immunology Immunotherapy",

issn = "0340-7004",

publisher = "Springer",

}

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, DA, Cheng, P, Dunn, W, Platt, F, Endou, H, Craddock, C, Keeshan, K, Mussai, F & De Santo, C 2022, 'Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment', Cancer Immunology Immunotherapy. https://doi.org/10.1007/s00262-022-03268-4

TY - JOUR

T1 - Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment

AU - Stavrou, Victoria

AU - Fultang, Livingstone

AU - Booth, Sarah

AU - De Simone, Daniele

AU - Bartnik, Arekdiusz

AU - Scarpa, Ugo

AU - Gneo, Luciana

AU - Panetti, Silvia

AU - Potluri, Sandeep

AU - Almowaled, Meaad

AU - Barlow, Jonathan

AU - Jankevics, Andris

AU - Lloyd, Gavin

AU - Southam, Andrew

AU - Priestman, David A.

AU - Cheng, Paul

AU - Dunn, Warwick

AU - Platt, Frances

AU - Endou, Hitoshi

AU - Craddock, Charles

AU - Keeshan, Karen

AU - Mussai, Francis

AU - De Santo, Carmela

N1 - 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).

PY - 2022/8/13

Y1 - 2022/8/13

N2 - 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.

AB - 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.

KW - iNKT

KW - AML

KW - ASS

KW - LAT-1

KW - Arginine

KW - Cancer

U2 - 10.1007/s00262-022-03268-4

DO - 10.1007/s00262-022-03268-4

M3 - Article

C2 - 35962843

SN - 0340-7004

JO - Cancer Immunology Immunotherapy

JF - Cancer Immunology Immunotherapy

ER -

Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment

Abstract

Bibliographical note

Keywords

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Projects

Integrating innovative technologies for genotyping in stratified medicine

Cite this