Kindlin-1 regulates IL-6 secretion and modulates the immune environment in breast cancer models
- University of Edinburgh, United Kingdom
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
Article and author information
Author details
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.
Reviewing Editor
- Tatyana Chtanova, Garvan Institute of Medical Research, Australia
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.
Version history
- Preprint posted: March 5, 2022 (view preprint)
- Received: December 21, 2022
- Accepted: March 8, 2023
- Accepted Manuscript published: March 8, 2023 (version 1)
- 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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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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