Cancer‐associated fibroblasts contribute to the immunosuppressive landscape and influence the efficacy of the combination therapy of PD‐1 inhibitors and antiangiogenic agents in hepatocellular carcinoma

Abstract

BackgroundChronic inflammation is considered the most critical predisposing factor of hepatocellular carcinoma (HCC), with inflammatory cell heterogeneity, hepatic fibrosis accumulation, and abnormal vascular proliferation as prominent features of the HCC tumor microenvironment (TME). Cancer‐associated fibroblasts (CAFs) play a key role in HCC TME remodeling. Therefore, the level of abundance of CAFs may significantly affect the prognosis and outcome in HCC patients.MethodsUnsupervised clustering was performed based on 39 genes related to CAFs in HCC identified by single‐cell RNA sequencing data. Patients of bulk RNA were grouped into CAF low abundance cluster and high abundance clusters. Subsequently, prognosis, immune infiltration landscape, metabolism, and treatment response between the two clusters were investigated and validated by immunohistochemistry.ResultsPatients in the CAF high cluster had a higher level of inflammatory cell infiltration, a more significant immunosuppressive microenvironment, and a significantly worse prognosis than those in the low cluster. At the metabolic level, the CAF high cluster had lower levels of aerobic oxidation and higher angiogenic scores. Drug treatment response prediction indicated that the CAF high cluster could have a better response to PD‐1 inhibitors and conventional chemotherapeutic agents for HCC such as anti‐angiogenic drugs, whereas CAF low cluster may be more sensitive to transarterial chemoembolization treatment.ConclusionsThis study not only revealed the TME characteristics of HCC with the difference in CAF abundance but also further confirmed that the combination therapy of PD‐1 inhibitors and anti‐angiogenic drugs may be more valuable for patients with high CAF abundance.

Fire and Oil Led to Complex Mixtures of PAHs on Burnt and Unburnt Plastic during the M/V X-Press Pearl Disaster

“…Nurdles from spills are endemic . Collecting all the spilled material is an unrealistic objective, posing the oft question, “How clean is clean?” , Following previous nurdle spills, cleanup efforts predominantly relied on community-based activities to recover spilled material. ,− After a spill in the North Sea, efforts focused on removing any piece of plastic from beaches . However, this is a false equivalency because different plastics behave differently in the environment.…”

Hepatocellular Carcinoma and the Multifaceted Relationship with Its Microenvironment: Attacking the Hepatocellular Carcinoma Defensive Fortress

“…Indeed, as demonstrated by Zhao J. et al [152], through the secretion of CXCL12, a chemokine that induces the upregulation of FOLR1 in HCC cells, CAFs contribute to resistance to sorafenib therapy. Concurrently, Chen Q et al have indicated that combination therapy involving PD-1 inhibitors and anti-angiogenic drugs may hold greater promise for patients with elevated CAF abundance compared to single-agent treatment strategies [153].…”

Research progress of exosomes in the angiogenesis of digestive system tumour

“…Hepatocellular carcinoma (HCC) cell-derived exosomal miRNA-21 directly targeted PTEN (gene of phosphate and tension homology deleted on chromosome ten), leading to the activation of PDK1/AKT signalling in Hepatic stellate cells (HSCs), which are then transformed into CAFs [ 127 ]. Activated CAFs further promote cancer angiogenesis by secreting angiogenic cytokines, including VEGF, MMP2, MMP9, bFGF and TGF-β [ 128 ]. Furthmore, miR-21 can also shape a vascular microenvironment for HCC via the STAT3/VEGF signalling pathway, and miR-221 can activate the SAND/NF-κB pathway to upregulate the expression of CXCL16, which is an angiogenic factor [ 129 ].…”