The programmed cell death protein 1 (PD-1) pathway has received considerable attention due to its role in eliciting the immune checkpoint response of T cells, resulting in tumor cells capable of evading immune surveillance and being highly refractory to conventional chemotherapy. Application of anti-PD-1/PD-L1 antibodies as checkpoint inhibitors is rapidly becoming a promising therapeutic approach in treating tumors, and some of them have successfully been commercialized in the past few years. However, not all patients show complete responses and adverse events have been noted, suggesting a better understanding of PD-1 pathway mediated immunosuppression is needed to predict patient response and improve treatment efficacy. Here, we review the progresses on the studies of the mechanistic role of PD-1 pathway in the tumor immune evasion, recent clinical development and commercialization of PD-1 pathway inhibitors, the toxicities associated with PD-1 blockade observed in clinical trials as well as how to improve therapeutic efficacy and safety of cancer immunotherapy.

Introduction: Increasing evidence demonstrates that long noncoding RNAs (lncRNAs) play important roles in the progression of hepatocellular carcinoma (HCC) by regulating gene expression. However, the identification of functional lncRNAs in HCC remains insufficient. Our study aimed to investigate the function of lncRNA OGFRP1, which has not been functionally researched before, in Hep3B and HepG2 cells. Methods: lncRNA OGFRP1 in HCC cells was down-regulated by using RNAi technology. Quantitative real-time polymerase chain reaction was used to determine the mRNA expression of lncRNA OGFRP1. Cell proliferation was examined by CCK8 and clone formation assays. Cell cycle and apoptosis were analyzed by flow cytometry. Cell migration and invasion were assessed by using Scratch assay and transwell assay, respectively. Protein expression of signaling pathways was determined by using Western blot. Results: Cell proliferation of Hep3B was significantly inhibited by down-regulation of lncRNA OGFRP1 (P<0.05). Moreover, siOGFRP1 transfection induced Hep3B cell cycle arrest and apoptosis by regulating the expression of related proteins. Cell migration and invasion of Hep3B were also significantly inhibited by down-regulation of lncRNA OGFRP1. Wnt/β-catenin signaling pathway, involved in epithelial–mesenchymal transition (EMT), was inactivated by lncRNA OGFRP1 downregulation, including decreased expression of Wnt3a, β-catenin, N-cadherin and vimentin and increased expression of E-cadherin. We also found that the inhibitory effect of lncRNA OGFRP1 knockdown on Hep3B was mediated by the AKT/mTOR signaling pathway and IGF-1, an AKT signaling activator, could rescue the cellular phenotype. However, knockdown of lncRNA OGFRP1 did not influence cell proliferation, migration and invasion in HepG2 cells. Conclusion: We found that downregulation of lncRNA OGFRP1 suppressed the proliferation and EMT of HCC Hep3B cells through AKT and Wnt/β-catenin signaling pathways. However, lncRNA OGFRP1 exhibited a differentiated function in different HCC cell lines, which required further study in the future.

Xu Z, et al. Korean J Radiol. 2020 Feb;21:e55. https://doi.org/10.3348/kjr.2019.0853

Intratumor microbiota are increasingly implicated in cancer pathogenesis, with emerging evidence suggesting their role in regulating DNA methylation pathways in hepatocellular carcinoma (HCC). This study investigates the interactions between specific bacterial genera and key DNA methylation-related genes in HCC tissues. Tumor and adjacent normal tissues from 72 HCC surgical patients were analyzed. Bacterial composition was characterized via 16SrRNA sequencing, while quantitative analysis assessed the abundance of differential bacterial genera and expression of DNA methylation pathway genes linked to HCC outcomes. Six bacterial genera exhibited differential abundance between tumor and normal tissues: Propionibacterium, Mycoplasma, Variovorax, OPB41, unclassified_Bifidobacteriaceae, and Rikenellaceae. Key gene-microbiota correlations included: Negative associations of Propionibacterium with SPOCD1 and EOMES; Negative associations of Mycoplasma with BMI1 and EZH2; Negative correlations of Pseudomonas with BMI1, EOMES, EZH2, and SPOCD1. Additionally, Pseudomonas abundance was negatively correlated with both Propionibacterium and Mycoplasma. The identified microbiota-gene interactions reveal potential mechanistic links between intratumor flora and HCC progression via DNA methylation regulation. These findings highlight novel targets for further exploration of HCC therapeutic strategies.