THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer
Abstract Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcom...
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| Format: | Article |
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Nature Portfolio
2023-09-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41095-y |
| _version_ | 1797558840892325888 |
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| author | Mayuki Omatsu Yuki Nakanishi Kosuke Iwane Naoki Aoyama Angeles Duran Yu Muta Anxo Martinez-Ordoñez Qixiu Han Nobukazu Agatsuma Kenta Mizukoshi Munenori Kawai Go Yamakawa Mio Namikawa Kensuke Hamada Yuichi Fukunaga Takahiro Utsumi Makoto Sono Tomonori Masuda Akitaka Hata Osamu Araki Munemasa Nagao Takaaki Yoshikawa Satoshi Ogawa Yukiko Hiramatsu Motoyuki Tsuda Takahisa Maruno Toshiaki Kogame Hiroaki Kasashima Nobuyuki Kakiuchi Masahiro M. Nakagawa Kenji Kawada Masakazu Yashiro Kiyoshi Maeda Yasuyuki Saito Takashi Matozaki Akihisa Fukuda Kenji Kabashima Kazutaka Obama Seishi Ogawa Nader Sheibani Maria T. Diaz-Meco Jorge Moscat Hiroshi Seno |
| author_facet | Mayuki Omatsu Yuki Nakanishi Kosuke Iwane Naoki Aoyama Angeles Duran Yu Muta Anxo Martinez-Ordoñez Qixiu Han Nobukazu Agatsuma Kenta Mizukoshi Munenori Kawai Go Yamakawa Mio Namikawa Kensuke Hamada Yuichi Fukunaga Takahiro Utsumi Makoto Sono Tomonori Masuda Akitaka Hata Osamu Araki Munemasa Nagao Takaaki Yoshikawa Satoshi Ogawa Yukiko Hiramatsu Motoyuki Tsuda Takahisa Maruno Toshiaki Kogame Hiroaki Kasashima Nobuyuki Kakiuchi Masahiro M. Nakagawa Kenji Kawada Masakazu Yashiro Kiyoshi Maeda Yasuyuki Saito Takashi Matozaki Akihisa Fukuda Kenji Kabashima Kazutaka Obama Seishi Ogawa Nader Sheibani Maria T. Diaz-Meco Jorge Moscat Hiroshi Seno |
| author_sort | Mayuki Omatsu |
| collection | DOAJ |
| description | Abstract Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis. |
| first_indexed | 2024-03-10T17:36:06Z |
| format | Article |
| id | doaj.art-faf191500a2f4f9e8f8e32b58ac4ba14 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:36:06Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-faf191500a2f4f9e8f8e32b58ac4ba142023-11-20T09:51:33ZengNature PortfolioNature Communications2041-17232023-09-0114111910.1038/s41467-023-41095-yTHBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancerMayuki Omatsu0Yuki Nakanishi1Kosuke Iwane2Naoki Aoyama3Angeles Duran4Yu Muta5Anxo Martinez-Ordoñez6Qixiu Han7Nobukazu Agatsuma8Kenta Mizukoshi9Munenori Kawai10Go Yamakawa11Mio Namikawa12Kensuke Hamada13Yuichi Fukunaga14Takahiro Utsumi15Makoto Sono16Tomonori Masuda17Akitaka Hata18Osamu Araki19Munemasa Nagao20Takaaki Yoshikawa21Satoshi Ogawa22Yukiko Hiramatsu23Motoyuki Tsuda24Takahisa Maruno25Toshiaki Kogame26Hiroaki Kasashima27Nobuyuki Kakiuchi28Masahiro M. Nakagawa29Kenji Kawada30Masakazu Yashiro31Kiyoshi Maeda32Yasuyuki Saito33Takashi Matozaki34Akihisa Fukuda35Kenji Kabashima36Kazutaka Obama37Seishi Ogawa38Nader Sheibani39Maria T. Diaz-Meco40Jorge Moscat41Hiroshi Seno42Department of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Dermatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Dermatology, Kyoto University Graduate School of MedicineDepartment of Gastroenterological Surgery, Osaka Metropolitan UniversityDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Pathology and Tumor Biology, Kyoto UniversityDepartment of Gastrointestinal Surgery, Kyoto University, Graduate School of MedicineDepartment of Gastroenterological Surgery, Osaka Metropolitan UniversityDepartment of Gastroenterological Surgery, Osaka Metropolitan UniversityDivision of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of MedicineDivision of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineDepartment of Dermatology, Kyoto University Graduate School of MedicineDepartment of Gastrointestinal Surgery, Kyoto University, Graduate School of MedicineDepartment of Pathology and Tumor Biology, Kyoto UniversityDepartment of Ophthalmology and Visual Sciences, University of Wisconsin-Department of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Gastroenterology and Hepatology, Kyoto University Graduate School of MedicineAbstract Mesenchymal activation, characterized by dense stromal infiltration of immune and mesenchymal cells, fuels the aggressiveness of colorectal cancers (CRC), driving progression and metastasis. Targetable molecules in the tumor microenvironment (TME) need to be identified to improve the outcome in CRC patients with this aggressive phenotype. This study reports a positive link between high thrombospondin-1 (THBS1) expression and mesenchymal characteristics, immunosuppression, and unfavorable CRC prognosis. Bone marrow-derived monocyte-like cells recruited by CXCL12 are the primary source of THBS1, which contributes to the development of metastasis by inducing cytotoxic T-cell exhaustion and impairing vascularization. Furthermore, in orthotopically generated CRC models in male mice, THBS1 loss in the TME renders tumors partially sensitive to immune checkpoint inhibitors and anti-cancer drugs. Our study establishes THBS1 as a potential biomarker for identifying mesenchymal CRC and as a critical suppressor of antitumor immunity that contributes to the progression of this malignancy with a poor prognosis.https://doi.org/10.1038/s41467-023-41095-y |
| spellingShingle | Mayuki Omatsu Yuki Nakanishi Kosuke Iwane Naoki Aoyama Angeles Duran Yu Muta Anxo Martinez-Ordoñez Qixiu Han Nobukazu Agatsuma Kenta Mizukoshi Munenori Kawai Go Yamakawa Mio Namikawa Kensuke Hamada Yuichi Fukunaga Takahiro Utsumi Makoto Sono Tomonori Masuda Akitaka Hata Osamu Araki Munemasa Nagao Takaaki Yoshikawa Satoshi Ogawa Yukiko Hiramatsu Motoyuki Tsuda Takahisa Maruno Toshiaki Kogame Hiroaki Kasashima Nobuyuki Kakiuchi Masahiro M. Nakagawa Kenji Kawada Masakazu Yashiro Kiyoshi Maeda Yasuyuki Saito Takashi Matozaki Akihisa Fukuda Kenji Kabashima Kazutaka Obama Seishi Ogawa Nader Sheibani Maria T. Diaz-Meco Jorge Moscat Hiroshi Seno THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer Nature Communications |
| title | THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer |
| title_full | THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer |
| title_fullStr | THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer |
| title_full_unstemmed | THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer |
| title_short | THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer |
| title_sort | thbs1 producing tumor infiltrating monocyte like cells contribute to immunosuppression and metastasis in colorectal cancer |
| url | https://doi.org/10.1038/s41467-023-41095-y |
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