Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling
Mechanical forces of the tumor microenvironment change dynamically during key events of tumorigenesis such as invasion and metastasis. These changes in compressive forces often affect the breast cancer cell phenotype. However, it is lesser known how these dynamic mechanical forces in the tumor microenvironment affect the phenotypes of tumor infiltrated leukocytes (TIL) and their subsequent anticancer activities. Here we find, in primary patient-derived explant cultures (PDEC) containing resident TILs, that low compression promotes a change in the original identity of breast cancer cells from luminal to a more mesenchymal and undifferentiated state. These altered tumor cells induce an upregulation of immunosuppressive cytokines such as interleukin-10 (IL-10) and Transforming Growth Factor Beta (TGF-β), as well as polarization of macrophages towards pro-tumor M2(Gc)-type and depletion of CD8+ effector memory T-cells. These immunosuppressive events are mediated by tumor cell derived fibroblast growth factor 2 (FGF2) and prostaglandin E2 (PGE2). We also find that FGF2 rich areas in primary tumors show enrichment in M2-like-macrophages and diminished numbers of CD8 + T and B-cells. Our results suggest that low compressive forces in the tumor microenvironment induce local immunosuppression via FGF2 secretion arising from phenotypic plasticity of tumor cells.
Authors
- Maria Heilala (ORCID: https://orcid.org/0000-0002-4237-4081)
- Topi A. Tervonen (ORCID: https://orcid.org/0000-0001-6577-9607)
- Panu E. Kovanen (ORCID: https://orcid.org/0000-0001-8218-2271)
- Tuomo J Meretoja (ORCID: https://orcid.org/0000-0002-2691-0710)
- Laura Niinikoski (ORCID: https://orcid.org/0000-0002-0838-2918)
- Maria Salmela (ORCID: https://orcid.org/0000-0003-1949-7101)
- Päivi Heikkilä (ORCID: https://orcid.org/0000-0002-8999-179X)
- Rita Turpin (ORCID: https://orcid.org/0000-0002-5094-5032)
- Pauliina Munne (ORCID: https://orcid.org/0000-0002-9720-9964)
- Johanna Mattson (ORCID: https://orcid.org/0000-0002-9719-9110)
- Minna Mutka (ORCID: https://orcid.org/0000-0002-8380-7293)
- Juha Klefström (ORCID: https://orcid.org/0000-0001-7124-8431)
- Maija Hollmén (ORCID: https://orcid.org/0000-0002-3250-7653)
- Ruixian Liu (ORCID: https://orcid.org/0000-0002-3065-6743)
- Aino Peura (ORCID: https://orcid.org/0000-0002-8958-940X)
- Piia Mikkonen
- July Aung (ORCID: https://orcid.org/0000-0003-4844-1289)
- Maritta Kilpeläinen
- Päivi Palanne
- Tiina Kantanen
- Outi Ukkonen
Institutions
- University of Helsinki (FI)
- University of Turku (FI)
- University of California, San Francisco (US)
- Helsinki University Hospital (FI)
- Finnish Environment Institute (FI)
- Turku University Hospital (FI)
- Finnish Cancer Registry (FI)
- UPM (Finland) (FI)
- Biocenter Finland (FI)
- Turku Centre for Biotechnology (FI)
- Cancer Society of Finland (FI)
- Kymenlaakson keskussairaala (FI)
- Hospital District of Helsinki and Uusimaa (FI)
- Aalto University (FI)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-27
- DOI
- https://doi.org/10.1038/s41467-025-60092-x
- Citations
- 5
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 5.23
Funders
- U.S. Department of Defense
- Helsingin ja Uudenmaan Sairaanhoitopiiri
- Suomen Lääketieteen Säätiö
- Finnish Cancer Institute
- European Commission
- Biomedicum Helsinki-säätiö
- Jane ja Aatos Erkon Säätiö
- Biocenter Finland
- Business Finland
- Helsinki Institute of Life Science, Helsingin Yliopisto
- Congressionally Directed Medical Research Programs