A1 Refereed original research article in a scientific journal
Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling
Authors: Peura, Aino; Turpin, Rita; Liu, Ruixian; Heilala, Maria; Salmela, Maria; Aung, July; Mikkonen, Piia; Mutka, Minna; Kovanen, Panu E.; Niinikoski, Laura; Meretoja, Tuomo; Mattson, Johanna; Heikkilä, Päivi; Palanne, Päivi; Kantanen, Tiina; Kilpeläinen, Mikko; Ukkonen, Outi; Hollmen, Maija; Tervonen, Topi A.; Klefström, Juha; Munne, Pauliina M.
Publisher: Springer Science and Business Media LLC
Publishing place: BERLIN
Publication year: 2025
Journal: Nature Communications
Journal name in source: Nature Communications
Journal acronym: NAT COMMUN
Article number: 4908
Volume: 16
Issue: 1
Number of pages: 17
eISSN: 2041-1723
DOI: https://doi.org/10.1038/s41467-025-60092-x
Web address : https://doi.org/10.1038/s41467-025-60092-x
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/499005009
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-beta), 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.
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We are grateful to the patients who participated in this study and made it possible, and to the personnel at Helsinki University Central Hospital who assisted with the recruitment of patients and collection of the sample material. We thank the Biomedicum Functional Genomics Unit (FuGU, HiLIFE, UH and Biocenter Finland) for their genome profiling services and the Biomedicum Imaging Unit (BIU, HiLIFE, UH, and Biocenter Finland) for the microscopy support. The authors would also like to thank FIMM Single-Cell Analytics unit supported by HiLIFE and Biocenter Finland for the single-cell analytics services. We also want to thank Annabrita Schoonenberg (FIMM Digital Microscopy and Molecular Pathology Unit supported by HiLIFE and Biocenter Finland) for performing the multiplex IHC staining. This study was funded by UPM Biomedicals and by grants from the Academy of Finland (JK), the Finnish Cancer Organization (JK), the Sigrid Juselius Foundation (JK), and Finnish Cancer Institute (FCI)(JK), Finnish Medical Foundation (AP), Jane and Aatos Erkko Foundation (JK), Biomedicum Helsinki Foundation (AP) and Eemil Aaltonen Foundation (AP). M. Heilala acknowledges funding from the Academy of Finland's Flagship Program under Projects No. 318890 and 318891 (Competence Center for Materials Bioeconomy, FinnCERES) and Finnish Foundation for Technology Promotion. Moreover, the work was funded by the Business Finland R2B funding (2489/31/2017, Preclinica; 42533/31/2020, Immunate), and the RESCUER project, which has received funding from the European Union's Horizon 2020 Research and Innovation Programme under Grant agreement No. 847912. This work was also supported by the CDMRP W81XWH211-0773/-0774. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. Illustrations 1 A, 4 A and 6 C were created by BioRender. Open access was funded by Helsinki University Library.
