Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas
Abstract T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and modulating immune infiltration. Despite the ident...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-46504-4 |
| _version_ | 1827310058031022080 |
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| author | Marina T. Broz Emily Y. Ko Kristin Ishaya Jinfen Xiao Marco De Simone Xen Ping Hoi Roberta Piras Basia Gala Fernando H. G. Tessaro Anja Karlstaedt Sandra Orsulic Amanda W. Lund Keith Syson Chan Jlenia Guarnerio |
| author_facet | Marina T. Broz Emily Y. Ko Kristin Ishaya Jinfen Xiao Marco De Simone Xen Ping Hoi Roberta Piras Basia Gala Fernando H. G. Tessaro Anja Karlstaedt Sandra Orsulic Amanda W. Lund Keith Syson Chan Jlenia Guarnerio |
| author_sort | Marina T. Broz |
| collection | DOAJ |
| description | Abstract T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and modulating immune infiltration. Despite the identification of distinct CAF subtypes using single-cell RNA-sequencing (scRNA-seq), their functional impact on hindering T-cell infiltration remains unclear, particularly in soft-tissue sarcomas (STS) characterized by low response rates to T cell-based therapies. In this study, we characterize the STS microenvironment using murine models (in female mice) with distinct immune composition by scRNA-seq, and identify a subset of CAFs we termed glycolytic cancer-associated fibroblasts (glyCAF). GlyCAF rely on GLUT1-dependent expression of CXCL16 to impede cytotoxic T-cell infiltration into the tumor parenchyma. Targeting glycolysis decreases T-cell restrictive glyCAF accumulation at the tumor margin, thereby enhancing T-cell infiltration and augmenting the efficacy of chemotherapy. These findings highlight avenues for combinatorial therapeutic interventions in sarcomas and possibly other solid tumors. Further investigations and clinical trials are needed to validate these potential strategies and translate them into clinical practice. |
| first_indexed | 2024-04-24T19:53:39Z |
| format | Article |
| id | doaj.art-3c3fee63de4c4625909fa4b34fc910c7 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-24T19:53:39Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-3c3fee63de4c4625909fa4b34fc910c72024-03-24T12:27:02ZengNature PortfolioNature Communications2041-17232024-03-0115111810.1038/s41467-024-46504-4Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomasMarina T. Broz0Emily Y. Ko1Kristin Ishaya2Jinfen Xiao3Marco De Simone4Xen Ping Hoi5Roberta Piras6Basia Gala7Fernando H. G. Tessaro8Anja Karlstaedt9Sandra Orsulic10Amanda W. Lund11Keith Syson Chan12Jlenia Guarnerio13Department of Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Radiation Oncology, Cedars-Sinai Medical CenterDepartment of Radiation Oncology, Cedars-Sinai Medical CenterDepartment of Radiation Oncology, Cedars-Sinai Medical CenterDepartment of Radiation Oncology, Cedars-Sinai Medical CenterDepartment of Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Biomedical Sciences, Cedars-Sinai Medical CenterDepartment of Radiation Oncology, Cedars-Sinai Medical CenterDepartment of Biomedical Sciences, Cedars-Sinai Medical CenterDavid Geffen Medical School, Department of Medicine, University of CaliforniaRonald O. Perelman Department of Dermatology, NYU Grossman School of MedicineDepartment of Urology, Neal Cancer Center, Houston Methodist Research InstituteDepartment of Biomedical Sciences, Cedars-Sinai Medical CenterAbstract T cell-based immunotherapies have exhibited promising outcomes in tumor control; however, their efficacy is limited in immune-excluded tumors. Cancer-associated fibroblasts (CAFs) play a pivotal role in shaping the tumor microenvironment and modulating immune infiltration. Despite the identification of distinct CAF subtypes using single-cell RNA-sequencing (scRNA-seq), their functional impact on hindering T-cell infiltration remains unclear, particularly in soft-tissue sarcomas (STS) characterized by low response rates to T cell-based therapies. In this study, we characterize the STS microenvironment using murine models (in female mice) with distinct immune composition by scRNA-seq, and identify a subset of CAFs we termed glycolytic cancer-associated fibroblasts (glyCAF). GlyCAF rely on GLUT1-dependent expression of CXCL16 to impede cytotoxic T-cell infiltration into the tumor parenchyma. Targeting glycolysis decreases T-cell restrictive glyCAF accumulation at the tumor margin, thereby enhancing T-cell infiltration and augmenting the efficacy of chemotherapy. These findings highlight avenues for combinatorial therapeutic interventions in sarcomas and possibly other solid tumors. Further investigations and clinical trials are needed to validate these potential strategies and translate them into clinical practice.https://doi.org/10.1038/s41467-024-46504-4 |
| spellingShingle | Marina T. Broz Emily Y. Ko Kristin Ishaya Jinfen Xiao Marco De Simone Xen Ping Hoi Roberta Piras Basia Gala Fernando H. G. Tessaro Anja Karlstaedt Sandra Orsulic Amanda W. Lund Keith Syson Chan Jlenia Guarnerio Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas Nature Communications |
| title | Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas |
| title_full | Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas |
| title_fullStr | Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas |
| title_full_unstemmed | Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas |
| title_short | Metabolic targeting of cancer associated fibroblasts overcomes T-cell exclusion and chemoresistance in soft-tissue sarcomas |
| title_sort | metabolic targeting of cancer associated fibroblasts overcomes t cell exclusion and chemoresistance in soft tissue sarcomas |
| url | https://doi.org/10.1038/s41467-024-46504-4 |
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