1. Cancer Biology

Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models

  1. Emily R Webb  Is a corresponding author
  2. Georgia L Dodd
  3. Michaela Noskova
  4. Esme Bullock
  5. Morwenna Muir
  6. Margaret C Frame
  7. Alan Serrels
  8. Valerie G Brunton  Is a corresponding author
  1. University of Edinburgh, United Kingdom
https://doi.org/10.7554/eLife.85739
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Cite this article
  1. Emily R Webb
  2. Georgia L Dodd
  3. Michaela Noskova
  4. Esme Bullock
  5. Morwenna Muir
  6. Margaret C Frame
  7. Alan Serrels
  8. Valerie G Brunton
(2023)
Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models
eLife 12:e85739.
https://doi.org/10.7554/eLife.85739
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Abstract

The adhesion protein Kindlin-1 is over-expressed in breast cancer where it is associated with metastasis-free survival; however, the mechanisms involved are poorly understood. Here, we report that Kindlin-1 promotes anti-tumor immune evasion in mouse models of breast cancer. Deletion of Kindlin-1 in Met-1 mammary tumor cells led to tumor regression following injection into immunocompetent hosts. This was associated with a reduction in tumor infiltrating Tregs. Similar changes in T cell populations were seen following depletion of Kindlin-1 in the polyomavirus middle T antigen (PyV MT)-driven mouse model of spontaneous mammary tumorigenesis. There was a significant increase in IL-6 secretion from Met-1 cells when Kindlin-1 was depleted and conditioned media from Kindlin-1-depleted cells led to a decrease in the ability of Tregs to suppress the proliferation of CD8+ T cells, which was dependent on IL-6. In addition, deletion of tumor-derived IL-6 in the Kindlin-1-depleted tumors reversed the reduction of tumor-infiltrating Tregs. Overall, these data identify a novel function for Kindlin-1 in regulation of anti-tumor immunity, and that Kindlin-1 dependent cytokine secretion can impact the tumor immune environment.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1, 2, 4, 5 and 6

The following previously published data sets were used

Article and author information

Author details

  1. Emily R Webb

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Emily.webb@ed.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9339-4544

  2. Georgia L Dodd

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.

  3. Michaela Noskova

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.

  4. Esme Bullock

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.

  5. Morwenna Muir

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.

  6. Margaret C Frame

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    Margaret C Frame, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5882-1942

  7. Alan Serrels

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4992-6077

  8. Valerie G Brunton

    Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    v.brunton@ed.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7778-8794

Funding

Cancer Research UK (C157/A24837)

  • Emily R Webb

Cancer Research UK (C157/A29279)

  • Emily R Webb
  • Georgia L Dodd
  • Michaela Noskova
  • Esme Bullock
  • Morwenna Muir
  • Margaret C Frame
  • Alan Serrels
  • Valerie G Brunton

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were carried out in compliance with UK Home Office regulations underproject licence PP7510272. All animal procedures were approved by the University of Edinburgh Animal Welfare & Ethical Review Body (AWERB) approval PL05-21, and in accordance with the principles of the 3Rs. Every effort was made to minimise suffering.

Reviewing Editor

  1. Tatyana Chtanova, Garvan Institute of Medical Research, Australia

Version history

  1. Preprint posted: March 5, 2022 (view preprint)
  2. Received: December 21, 2022
  3. Accepted: March 8, 2023
  4. Accepted Manuscript published: March 8, 2023 (version 1)
  5. Version of Record published: March 17, 2023 (version 2)

Copyright

© 2023, Webb et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Emily R Webb
  2. Georgia L Dodd
  3. Michaela Noskova
  4. Esme Bullock
  5. Morwenna Muir
  6. Margaret C Frame
  7. Alan Serrels
  8. Valerie G Brunton
(2023)
Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models
eLife 12:e85739.
https://doi.org/10.7554/eLife.85739

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