THBS1-producing Tumor-infiltrating Monocyte-like Cells Contribute to Immunosuppression and Metastasis in Colorectal Cancer

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Sep 25

PMID 37749092

Authors

Mayuki Omatsu

Yuki Nakanishi

Kosuke Iwane

Naoki Aoyama

Angeles Duran

Yu Muta

Anxo Martinez-Ordonez

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

Affiliations

Soon will be listed here.

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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