Targeting integrin α5 in fibroblasts potentiates colorectal cancer response to PD-L1 blockade by affecting extracellular-matrix deposition

作者：Ling Lü, Yaohui Gao, Dengfeng Huang, Hu Liu, Dingzi Yin, Man Li, Jiayi Zheng, Shufei Wang, Weijun Wu, Li Zhao, Dexi Bi, Youhua Zhang, Feifei Song, Ruting Xie, Jifeng Wang, Huanlong Qin, Qing Wei · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2023 · DOI：10.1136/jitc-2023-007447 · 被引用次数：40 · 研究领域：Cell Adhesion Molecules Research、Cancer Cells and Metastasis、Cancer Immunotherapy and Biomarkers

Background One reason patients with cancer cannot benefit from immunotherapy is the lack of immune cell infiltration in tumor tissues. Cancer-associated fibroblasts (CAFs) are emerging as central players in immune regulation that shapes tumor microenvironment (TME). Earlier we reported that integrin α5 was enriched in CAFs in colorectal cancer (CRC), however, its role in TME and cancer immunotherapy remains unclear. Here, we aimed to investigate the role for integrin α5 in fibroblasts in modulating antitumor immunity and therapeutic efficacy combined with checkpoint blockade in CRC. Methods We analyzed the CRC single-cell RNA sequencing (scRNA-seq) database to define the expression of ITGA5 in CRC tumor stroma. Experimentally, we carried out in vivo mouse tumor xenograft models to confirm the targeting efficacy of combined α5β1 inhibition and anti-Programmed death ligand 1 (PD-L1) blockade and in vitro cell-co-culture assay to investigate the role of α5 in fibroblasts in affecting T-cell activity. Clinically, we analyzed the association between α5 expression and infiltrating T cells and evaluated their correlation with patient survival and immunotherapy prognosis in CRC. Results We revealed that ITGA5 was enriched in FAP -CAFs. Both ITGA5 knockout fibroblasts and therapeutic targeting of α5 improved response to anti-PD-L1 treatment in mouse subcutaneous tumor models. Mechanistically, these treatments led to increased tumor-infiltrating CD8 + T cells. Furthermore, we found tha...