THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer

  • Nat Commun. 2023 Sep 25;14(1):5534. doi: 10.1038/s41467-023-41095-y.
Mayuki Omatsu  1 ,  Yuki Nakanishi  2 ,  Kosuke Iwane  1 ,  Naoki Aoyama  1 ,  Angeles Duran  3 ,  Yu Muta  3  1 ,  Anxo Martinez-Ordoñez  3 ,  Qixiu Han  3 ,  Nobukazu Agatsuma  1 ,  Kenta Mizukoshi  1 ,  Munenori Kawai  1 ,  Go Yamakawa  1 ,  Mio Namikawa  1 ,  Kensuke Hamada  1 ,  Yuichi Fukunaga  1  4 ,  Takahiro Utsumi  1 ,  Makoto Sono  1 ,  Tomonori Masuda  1 ,  Akitaka Hata  5 ,  Osamu Araki  1 ,  Munemasa Nagao  1 ,  Takaaki Yoshikawa  1 ,  Satoshi Ogawa  1 ,  Yukiko Hiramatsu  1 ,  Motoyuki Tsuda  1 ,  Takahisa Maruno  1 ,  Toshiaki Kogame  5 ,  Hiroaki Kasashima  6 ,  Nobuyuki Kakiuchi  1  7 ,  Masahiro M Nakagawa  8 ,  Kenji Kawada  9 ,  Masakazu Yashiro  6 ,  Kiyoshi Maeda  6 ,  Yasuyuki Saito  10 ,  Takashi Matozaki  10  11 ,  Akihisa Fukuda  1 ,  Kenji Kabashima  5 ,  Kazutaka Obama  9 ,  Seishi Ogawa  8 ,  Nader Sheibani  12 ,  Maria T Diaz-Meco  3 ,  Jorge Moscat  3 ,  Hiroshi Seno  1
Affiliations
  • 1. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 2. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. [email protected].
  • 3. Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, USA.
  • 4. Cancer Research Unit, Sumitomo Pharma Co., Ltd, Osaka, Japan.
  • 5. Department of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 6. Department of Gastroenterological Surgery, Osaka Metropolitan University, Osaka, Japan.
  • 7. The Hakubi Center for Advanced Research, Kyoto University, Kyoto, Japan.
  • 8. Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.
  • 9. Department of Gastrointestinal Surgery, Kyoto University, Graduate School of Medicine, Kyoto, Japan.
  • 10. Division of Molecular and Cellular Signaling, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
  • 11. Division of Biosignal Regulation, Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
  • 12. Department of Ophthalmology and Visual Sciences, University of Wisconsin-, Madison, Wisconsin, USA.
PMID: 37749092 DOI: 10.1038/s41467-023-41095-y
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.

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