2. Academic Validation
  3. M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism

M2 macrophages drive leukemic transformation by imposing resistance to phagocytosis and improving mitochondrial metabolism

  • Sci Adv. 2023 Apr 14;9(15):eadf8522. doi: 10.1126/sciadv.adf8522.
Isabel Weinhäuser 1 2 3,  Diego A Pereira-Martins 1 2 3,  Luciana Y Almeida 2,  Jacobien R Hilberink 1,  Douglas R A Silveira 4,  Lynn Quek 4,  Cesar Ortiz 2 3,  Cleide L Araujo 2,  Thiago M Bianco 2,  Antonio Lucena-Araujo 5,  Jose Mauricio Mota 6,  Shanna M Hogeling 1,  Dominique Sternadt 1,  Nienke Visser 1,  Arjan Diepstra 7,  Emanuele Ammatuna 1,  Gerwin Huls 1,  Eduardo M Rego 3,  Jan Jacob Schuringa 1
Affiliations

Affiliations

  • 1 Department of Experimental Hematology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands.
  • 2 Department of Internal Medicine, Medical School of Ribeirao Preto, University of São Paulo, Ribeirao Preto, Brazil.
  • 3 Center for Cell Based Therapy, University of São Paulo, Ribeirao Preto, Brazil.
  • 4 Myeloid Leukaemia Genomics and Biology Group, School of Cancer and Pharmaceutical Sciences, King's College London, London, SE5 8AF, UK.
  • 5 Department of Genetics, Federal University of Pernambuco, Recife, Brazil.
  • 6 Medical Oncology Service, Sao Paulo State Cancer Institute, University of Sao Paulo, Brazil.
  • 7 Department of Pathology and Medical Biology, Cancer Research Centre Groningen, University Medical Centre Groningen, University of Groningen, Groningen, Netherlands.
PMID: 37058562 DOI: 10.1126/sciadv.adf8522
Abstract

It is increasingly becoming clear that cancers are a symbiosis of diverse cell types and tumor clones. Combined single-cell RNA sequencing, flow cytometry, and immunohistochemistry studies of the innate immune compartment in the bone marrow of patients with acute myeloid leukemia (AML) reveal a shift toward a tumor-supportive M2-polarized macrophage landscape with an altered transcriptional program, with enhanced fatty acid oxidation and NAD+ generation. Functionally, these AML-associated macrophages display decreased phagocytic activity and intra-bone marrow coinjection of M2 macrophages together with leukemic blasts strongly enhances in vivo transformation potential. A 2-day in vitro exposure to M2 macrophages results in the accumulation of CALRlow leukemic blast cells, which are now protected against phagocytosis. Moreover, M2-exposed "trained" leukemic blasts display increased Mitochondrial Metabolism, in part mediated via mitochondrial transfer. Our study provides insight into the mechanisms by which the immune landscape contributes to aggressive leukemia development and provides alternatives for targeting strategies aimed at the tumor microenvironment.

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