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  • [Cancer Res.] 종양저산소환경 및 대사변화에서의 TAM세포의 역할연구Tumor-associated macrophages enhance tumor hypoxia and aerobic glycolysis.

    포항공대 / 정회빈, 안지완*

  • 출처
    Cancer Res.
  • 등재일
    2019 Jan 4. pii: canres.2545.2018. doi: 10.1158/00
  • 저널이슈번호
  • 내용

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    Abstract
    Tumor hypoxia and aerobic glycolysis are well-known resistance factors for anticancer therapies. Here we demonstrate that tumor-associated macrophages (TAM) enhance tumor hypoxia and aerobic glycolysis in mice subcutaneous tumors and in non-small cell lung cancer (NSCLC) patients. We found a strong correlation between CD68 TAM immunostaining and positron emission tomography (PET) 18fluoro-deoxyglucose (FDG) uptake in 98 matched tumors of NSCLC patients. We also observed a significant correlation between CD68 and glycolytic gene signatures in 513 NSCLC patients from the TCGA database. TAM secreted tumor necrosis factor-α (TNF-α) to promote tumor cell glycolysis while increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in TAM facilitated tumor hypoxia. Depletion of TAM by clodronate was sufficient to abrogate aerobic glycolysis and tumor hypoxia, thereby improving tumor response to anticancer therapies. TAM depletion led to a significant increase in programmed death-ligand 1 (PD-L1) expression in aerobic cancer cells as well as T cell infiltration in tumors, resulting in antitumor efficacy by PD-L1 antibodies which were otherwise completely ineffective. These data suggest that TAM can significantly alter tumor metabolism, further complicating tumor response to anticancer therapies including immunotherapy.

     


    Author information

    Jeong H1, Kim S2, Hong BJ1, Lee CJ1, Kim YE1, Bok S1, Oh JM1, Gwak SH1, Yoo MY3, Lee MS3, Chung SJ3, Defrêne J4, Tessier P4, Pelletier M4, Jeon H5, Roh TY5, Kim B6, Kim KH7, Ju JH8, Kim S9, Lee YJ10, Kim DW11, Kim IH12, Kim HJ13, Park JW14, Lee YS3, Lee JS3, Cheon GJ3, Weissman IL15, Chung DH16, Jeon YK17, Ahn GO18.
    1
    Division of Integrative Bioscience and Biotechnology, POSTECH.
    2
    Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine.
    3
    Department of Nuclear Medicine, Seoul National University College of Medicine.
    4
    Department of Microbiology-Infectious Disease and Immunology, Laval University.
    5
    Department of Life Science, POSTECH.
    6
    Division of Integrative Biosciences and Biotechnology, POSTECH.
    7
    Department of Mechanical Engineering, POSTECH.
    8
    Division of Rheumatology, Catholic University of Korea.
    9
    Department of Chemistry, Pohang University of Science and Technology.
    10
    Division of Radiation Biomedical Research, Korea Instituteof Radiological and Medical Sciences.
    11
    Internal Medicine, Seoul National University Hospital.
    12
    Radiation Oncology, Seoul National University.
    13
    Department of Radiation Oncology, Seoul National University College of Medicine.
    14
    Pharmacology, Seoul National University College of Medicine.
    15
    Institute of Stem Cell Biology and Regenerative Medicine, Stanford University.
    16
    Pathology, Seoul National University.
    17
    Department of Pathology, Seoul National University College of Medicine.
    18
    Integrative Biosciences and Biotechnology, Pohang University of Science and Technology goneahn@gmail.com.

  • 편집위원

    Hypoxia와 aerobic glycolysis는 항암치료의 저항성을 유발하는 주요한 인자다. 본 연구에서는 TAM(tumor-associated macrophages)이 tumor microenvironment와 metabolism의 변화를 유도하여 치료효율을 저하시키는데 관여함을 규명하였다.

    2019-02-22 17:34:48

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