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

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 and Hiroshi Seno
Additional contact information
Mayuki Omatsu: Kyoto University Graduate School of Medicine
Yuki Nakanishi: Kyoto University Graduate School of Medicine
Kosuke Iwane: Kyoto University Graduate School of Medicine
Naoki Aoyama: Kyoto University Graduate School of Medicine
Angeles Duran: Weill Cornell Medicine
Yu Muta: Weill Cornell Medicine
Anxo Martinez-Ordoñez: Weill Cornell Medicine
Qixiu Han: Weill Cornell Medicine
Nobukazu Agatsuma: Kyoto University Graduate School of Medicine
Kenta Mizukoshi: Kyoto University Graduate School of Medicine
Munenori Kawai: Kyoto University Graduate School of Medicine
Go Yamakawa: Kyoto University Graduate School of Medicine
Mio Namikawa: Kyoto University Graduate School of Medicine
Kensuke Hamada: Kyoto University Graduate School of Medicine
Yuichi Fukunaga: Kyoto University Graduate School of Medicine
Takahiro Utsumi: Kyoto University Graduate School of Medicine
Makoto Sono: Kyoto University Graduate School of Medicine
Tomonori Masuda: Kyoto University Graduate School of Medicine
Akitaka Hata: Kyoto University Graduate School of Medicine
Osamu Araki: Kyoto University Graduate School of Medicine
Munemasa Nagao: Kyoto University Graduate School of Medicine
Takaaki Yoshikawa: Kyoto University Graduate School of Medicine
Satoshi Ogawa: Kyoto University Graduate School of Medicine
Yukiko Hiramatsu: Kyoto University Graduate School of Medicine
Motoyuki Tsuda: Kyoto University Graduate School of Medicine
Takahisa Maruno: Kyoto University Graduate School of Medicine
Toshiaki Kogame: Kyoto University Graduate School of Medicine
Hiroaki Kasashima: Osaka Metropolitan University
Nobuyuki Kakiuchi: Kyoto University Graduate School of Medicine
Masahiro M. Nakagawa: Kyoto University
Kenji Kawada: Kyoto University, Graduate School of Medicine
Masakazu Yashiro: Osaka Metropolitan University
Kiyoshi Maeda: Osaka Metropolitan University
Yasuyuki Saito: Kobe University Graduate School of Medicine
Takashi Matozaki: Kobe University Graduate School of Medicine
Akihisa Fukuda: Kyoto University Graduate School of Medicine
Kenji Kabashima: Kyoto University Graduate School of Medicine
Kazutaka Obama: Kyoto University, Graduate School of Medicine
Seishi Ogawa: Kyoto University
Nader Sheibani: University of Wisconsin-
Maria T. Diaz-Meco: Weill Cornell Medicine
Jorge Moscat: Weill Cornell Medicine
Hiroshi Seno: Kyoto University Graduate School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41095-y

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