Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade

Atsushi Mitsuhashi; Kazuya Koyama; Hirokazu Ogino; Tania Afroj; Na Thi Nguyen; Hiroto Yoneda; Kenji Otsuka; Masamichi Sugimoto; Osamu Kondoh; Hiroshi Nokihara; Masaki Hanibuchi; Hiromitsu Takizawa; Tsutomu Shinohara; Yasuhiko Nishioka

doi:10.1016/j.celrep.2023.112162

Identification of fibrocyte cluster in tumors reveals the role in antitumor immunity by PD-L1 blockade

Cell Rep. 2023 Mar 28;42(3):112162. doi: 10.1016/j.celrep.2023.112162. Epub 2023 Mar 3.

Affiliations

¹ Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan.
² Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, Kamakura 247-8530, Japan.
³ Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan; Department of Community Medicine for Respirology, Hematology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan.
⁴ Department of Thoracic and Endocrine Surgery and Oncology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan.
⁵ Department of Community Medicine for Respirology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan.
⁶ Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan; Department of Community Medicine for Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8503, Japan. Electronic address: yasuhiko@tokushima-u.ac.jp.

PMID: 36870329
DOI: 10.1016/j.celrep.2023.112162

Abstract

Recent clinical trials revealed that immune checkpoint inhibitors and antiangiogenic reagent combination therapy improved the prognosis of various cancers. We investigated the roles of fibrocytes, collagen-producing monocyte-derived cells, in combination immunotherapy. Anti-VEGF (vascular endothelial growth factor) antibody increases tumor-infiltrating fibrocytes and enhances the antitumor effects of anti-PD-L1 (programmed death ligand 1) antibody in vivo. Single-cell RNA sequencing of tumor-infiltrating CD45⁺ cells identifies a distinct "fibrocyte cluster" from "macrophage clusters" in vivo and in lung adenocarcinoma patients. A sub-clustering analysis reveals a fibrocyte sub-cluster that highly expresses co-stimulatory molecules. CD8⁺ T cell-costimulatory activity of tumor-infiltrating CD45⁺CD34⁺ fibrocytes is enhanced by anti-PD-L1 antibody. Peritumoral implantation of fibrocytes enhances the antitumor effect of PD-L1 blockade in vivo; CD86^-/- fibrocytes do not. Tumor-infiltrating fibrocytes acquire myofibroblast-like phenotypes through transforming growth factor β (TGF-β)/small mothers against decapentaplegic (SMAD) signaling. Thus, TGF-βR/SMAD inhibitor enhances the antitumor effects of dual VEGF and PD-L1 blockade by regulating fibrocyte differentiation. Fibrocytes are highlighted as regulators of the response to programmed death 1 (PD-1)/PD-L1 blockade.

Keywords: CD86; CP: Cancer; CP: Immunology; PD-L1; TGF-β; VEGF; angiogenesis; combination immunotherapy; fibroblast; fibrocyte; immune checkpoint; tumor immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen
Humans
Immunotherapy
Neoplasms* / pathology
Tumor Microenvironment
Vascular Endothelial Growth Factor A* / pharmacology

Substances

CD274 protein, human
Vascular Endothelial Growth Factor A
B7-H1 Antigen