Head and neck squamous cell carcinoma cell lines have an immunomodulatory effect on macrophages independent of hypoxia and toll-like receptor ... View Full Text


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Article Info

DATE

2021-09-03

AUTHORS

Tamiko Ishizu, Dominik Eichin, Artur Padzik, Sanni Tuominen, Reidar Grénman, Marko Salmi, Tove J. Grönroos, Johanna M. Tuomela

ABSTRACT

BackgroundA low tissue oxygen level, < 1% O2, is a typical characteristic inside of solid tumors in head and neck cancer (HNSCC) affecting a wide array of cell populations, such as macrophages. However, the mechanisms of how hypoxia influences macrophages are not yet fully elucidated. Our research aimed to study the effect of soluble mediators produced by hypoxic cancer cells on macrophage polarization. Furthermore, we studied the effect of a hypoxic microenvironment on the expression of tumorigenic toll-like receptor 9 (TLR9) and the consecutive macrophage polarization.MethodsConditioned media (CMNOX or CMHOX) from cell lines UT-SCC-8, UT-SCC-74A, FaDu, MDA-MB-231 and HaCat cultured under normoxic (21% O2) and hypoxic (1% O2) conditions were used to polarize human monocyte-derived macrophages. Macrophage polarization was measured by flow cytometry and the production of cytokine mRNA using Taqman qPCR. To study the role of TLR9 in macrophage polarization, the lentiviral CRISPR/Cas9 method was used to establish a stable FaDuTLR9def clone.ResultsOur results demonstrate that the soluble mediators produced by the cancer cells under normoxia polarize macrophages towards a hybridized M1/M2a/M2c phenotype. Furthermore, the results suggest that hypoxia has a limited role in altering the array of cancer-produced soluble factors affecting macrophage polarization and cytokine production. Our data also indicates that increased expression of TLR9 due to hypoxia in malignant cells does not markedly influence the polarization of macrophages. TLR9 transcriptional response to hypoxia is dissimilar to a HIF1-α-regulated LDH-A. This may indicate a context-dependent expression of TLR9 under hypoxia.ConclusionsHNSCC cell lines affect both macrophage activity (polarization) and functionality (cytokines), but with exception to iNOS expression, the effects appear independent of hypoxia and TLR9. More... »

PAGES

990

References to SciGraph publications

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    http://scigraph.springernature.com/pub.10.1186/s12885-021-08357-8

    DOI

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    33 schema:description BackgroundA low tissue oxygen level, < 1% O2, is a typical characteristic inside of solid tumors in head and neck cancer (HNSCC) affecting a wide array of cell populations, such as macrophages. However, the mechanisms of how hypoxia influences macrophages are not yet fully elucidated. Our research aimed to study the effect of soluble mediators produced by hypoxic cancer cells on macrophage polarization. Furthermore, we studied the effect of a hypoxic microenvironment on the expression of tumorigenic toll-like receptor 9 (TLR9) and the consecutive macrophage polarization.MethodsConditioned media (CMNOX or CMHOX) from cell lines UT-SCC-8, UT-SCC-74A, FaDu, MDA-MB-231 and HaCat cultured under normoxic (21% O2) and hypoxic (1% O2) conditions were used to polarize human monocyte-derived macrophages. Macrophage polarization was measured by flow cytometry and the production of cytokine mRNA using Taqman qPCR. To study the role of TLR9 in macrophage polarization, the lentiviral CRISPR/Cas9 method was used to establish a stable FaDuTLR9def clone.ResultsOur results demonstrate that the soluble mediators produced by the cancer cells under normoxia polarize macrophages towards a hybridized M1/M2a/M2c phenotype. Furthermore, the results suggest that hypoxia has a limited role in altering the array of cancer-produced soluble factors affecting macrophage polarization and cytokine production. Our data also indicates that increased expression of TLR9 due to hypoxia in malignant cells does not markedly influence the polarization of macrophages. TLR9 transcriptional response to hypoxia is dissimilar to a HIF1-α-regulated LDH-A. This may indicate a context-dependent expression of TLR9 under hypoxia.ConclusionsHNSCC cell lines affect both macrophage activity (polarization) and functionality (cytokines), but with exception to iNOS expression, the effects appear independent of hypoxia and TLR9.
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    40 FaDu
    41 HIF1
    42 HaCaT
    43 LDH
    44 M2c phenotype
    45 MDA-MB-231
    46 O2
    47 ResultsOur results
    48 TaqMan qPCR
    49 Toll-like receptor 9
    50 UT-SCC
    51 activity
    52 array
    53 cancer
    54 cancer cells
    55 carcinoma cell lines
    56 cell carcinoma cell lines
    57 cell lines
    58 cell populations
    59 cells
    60 clones
    61 conditions
    62 context-dependent expression
    63 cytokine mRNA
    64 cytokine production
    65 cytometry
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    70 factors
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    72 functionality
    73 head
    74 human monocyte-derived macrophages
    75 hypoxia
    76 hypoxic cancer cells
    77 hypoxic conditions
    78 hypoxic microenvironment
    79 iNOS expression
    80 immunomodulatory effects
    81 levels
    82 limited role
    83 lines
    84 low tissue oxygen levels
    85 mRNA
    86 macrophage activity
    87 macrophage polarization
    88 macrophages
    89 malignant cells
    90 mechanism
    91 mediators
    92 medium
    93 method
    94 microenvironment
    95 monocyte-derived macrophages
    96 neck cancer
    97 neck squamous cell carcinoma cell lines
    98 normoxia
    99 oxygen levels
    100 phenotype
    101 polarization
    102 polarization of macrophages
    103 population
    104 production
    105 qPCR
    106 receptor 9
    107 research
    108 response
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    111 solid tumors
    112 soluble factors
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    114 squamous cell carcinoma cell lines
    115 tissue oxygen levels
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