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

Autor: Mitsuhashi, Atsushi, Koyama, Kazuya, Ogino, Hirokazu, Afroj, Tania, Nguyen, Na Thi, Yoneda, Hiroto, Otsuka, Kenji, Sugimoto, Masamichi, Kondoh, Osamu, Nokihara, Hiroshi, Hanibuchi, Masaki, Takizawa, Hiromitsu, Shinohara, Tsutomu, Nishioka, Yasuhiko
Zdroj: Cell Reports; March 2023, Vol. 42 Issue: 3
Abstrakt: 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 vivoand 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.
Databáze: Supplemental Index