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Targeting MARCO and...
Targeting MARCO and IL-37R on immunosuppressive macrophages in lung cancer blocks regulatory T cells and supports cytotoxic lymphocyte function
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- La Fleur, Linnea (author)
- Uppsala universitet,Klinisk och experimentell patologi,Science for Life Laboratory, SciLifeLab,Johan Botling
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- Botling, Johan (author)
- Uppsala universitet,Klinisk och experimentell patologi,Science for Life Laboratory, SciLifeLab,Johan Botling
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He, Fei (author)
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Pelicano, Catarina (author)
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- Zhou, Chikai (author)
- Karolinska Institutet
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He, Chenfei (author)
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- Palano, Giorgia (author)
- Karolinska Institutet
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- Mezheyeuski, Artur (author)
- Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab
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- Micke, Patrick (author)
- Uppsala universitet,Klinisk och experimentell patologi,Science for Life Laboratory, SciLifeLab,Patrick Micke
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Ravetch, Jeffrey V (author)
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- Karlsson, Mikael C I (author)
- Karolinska Institutet
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- Sarhan, Dhifaf (author)
- Karolinska Institutet
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(creator_code:org_t)
- American Association For Cancer Research (AACR), 2021
- 2021
- English.
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In: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 81:4, s. 956-967
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Subject headings
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- The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non-small cell lung cancer (NSCLC), accumulation of anti-inflammatory tumor-associated macrophages (TAMs) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of pro-tumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased Natural Killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL-37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL-37. MARCO-expressing TAMs blocked cytotoxic T cell and NK cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL-10 production and diminished CD8 T cell activities. Targeting MARCO or IL-37 receptor (IL-37R) by antibody or CRISPR knockout of IL-37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and anti-tumoral capacity of NK cells and T cells and down-modulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK and T cell anti-tumor activities.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Klinisk laboratoriemedicin (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Clinical Laboratory Medicine (hsv//eng)
Keyword
- Pathology
- Patologi
Publication and Content Type
- ref (subject category)
- art (subject category)
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To the university's database
- By the author/editor
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La Fleur, Linnea
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Botling, Johan
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He, Fei
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Pelicano, Catari ...
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Zhou, Chikai
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He, Chenfei
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show more...
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Palano, Giorgia
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Mezheyeuski, Art ...
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Micke, Patrick
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Ravetch, Jeffrey ...
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Karlsson, Mikael ...
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Sarhan, Dhifaf
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Clinical Laborat ...
- Articles in the publication
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Cancer Research
- By the university
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Uppsala University
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Karolinska Institutet