Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling
Abstract 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 tu...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60092-x |
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| author | Aino Peura Rita Turpin Ruixian Liu Maria Heilala Maria Salmela July Aung Piia Mikkonen Minna Mutka Panu E. Kovanen Laura Niinikoski Tuomo Meretoja Johanna Mattson Päivi Heikkilä Päivi Palanne Tiina Kantanen Mikko Kilpeläinen Outi Ukkonen Maija Hollmén Topi A. Tervonen Juha Klefström Pauliina M. Munne |
| author_facet | Aino Peura Rita Turpin Ruixian Liu Maria Heilala Maria Salmela July Aung Piia Mikkonen Minna Mutka Panu E. Kovanen Laura Niinikoski Tuomo Meretoja Johanna Mattson Päivi Heikkilä Päivi Palanne Tiina Kantanen Mikko Kilpeläinen Outi Ukkonen Maija Hollmén Topi A. Tervonen Juha Klefström Pauliina M. Munne |
| author_sort | Aino Peura |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-3b5b83b5b06e456d91570d268faa2ade |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-3b5b83b5b06e456d91570d268faa2ade2025-08-20T02:00:09ZengNature PortfolioNature Communications2041-17232025-05-0116111710.1038/s41467-025-60092-xSoft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signalingAino Peura0Rita Turpin1Ruixian Liu2Maria Heilala3Maria Salmela4July Aung5Piia Mikkonen6Minna Mutka7Panu E. Kovanen8Laura Niinikoski9Tuomo Meretoja10Johanna Mattson11Päivi Heikkilä12Päivi Palanne13Tiina Kantanen14Mikko Kilpeläinen15Outi Ukkonen16Maija Hollmén17Topi A. Tervonen18Juha Klefström19Pauliina M. Munne20Cancer Cell Circuitry Laboratory, Translational Cancer Medicine Research Program, Research Programs Unit, & Medicum, University of HelsinkiCancer Cell Circuitry Laboratory, Translational Cancer Medicine Research Program, Research Programs Unit, & Medicum, University of HelsinkiCancer Cell Circuitry Laboratory, Translational Cancer Medicine Research Program, Research Programs Unit, & Medicum, University of HelsinkiDepartment of Applied Physics, Aalto UniversityFinnish Genome Editing Center, HiLIFE infrastructures, University of Helsinki and Biocenter FinlandCancer Cell Circuitry Laboratory, Translational Cancer Medicine Research Program, Research Programs Unit, & Medicum, University of HelsinkiUPM Biomedicals, UPM-Kymmene CorporationDepartment of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of HelsinkiDepartment of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of HelsinkiBreast Surgery Unit, Comprehensive Cancer Center, Helsinki University Hospital and University of HelsinkiBreast Surgery Unit, Comprehensive Cancer Center, Helsinki University Hospital and University of HelsinkiComprehensive Cancer Center, University of Helsinki & Helsinki University HospitalDepartment of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of HelsinkiDepartment of Surgery, Kymenlaakso Central Hospital, KYMSOTEDepartment of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of HelsinkiDepartment of Surgery, Kymenlaakso Central Hospital, KYMSOTEDepartment of Surgery, Kymenlaakso Central Hospital, KYMSOTEMedicity Research Laboratory, University of Turku, Tykistökatu 6ACancer Cell Circuitry Laboratory, Translational Cancer Medicine Research Program, Research Programs Unit, & Medicum, University of HelsinkiCancer Cell Circuitry Laboratory, Translational Cancer Medicine Research Program, Research Programs Unit, & Medicum, University of HelsinkiCancer Cell Circuitry Laboratory, Translational Cancer Medicine Research Program, Research Programs Unit, & Medicum, University of HelsinkiAbstract 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.https://doi.org/10.1038/s41467-025-60092-x |
| spellingShingle | Aino Peura Rita Turpin Ruixian Liu Maria Heilala Maria Salmela July Aung Piia Mikkonen Minna Mutka Panu E. Kovanen Laura Niinikoski Tuomo Meretoja Johanna Mattson Päivi Heikkilä Päivi Palanne Tiina Kantanen Mikko Kilpeläinen Outi Ukkonen Maija Hollmén Topi A. Tervonen Juha Klefström Pauliina M. Munne Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling Nature Communications |
| title | Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling |
| title_full | Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling |
| title_fullStr | Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling |
| title_full_unstemmed | Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling |
| title_short | Soft matrix promotes immunosuppression in tumor-resident immune cells via COX-FGF2 signaling |
| title_sort | soft matrix promotes immunosuppression in tumor resident immune cells via cox fgf2 signaling |
| url | https://doi.org/10.1038/s41467-025-60092-x |
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