학술논문
THBS1-producing tumor-infiltrating monocyte-like cells contribute to immunosuppression and metastasis in colorectal cancer
Document Type
article
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
Source
Nature Communications, Vol 14, Iss 1, Pp 1-19 (2023)
Subject
Language
English
ISSN
2041-1723
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.