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
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.