Oncolytic virotherapy in cancer treatment: challenges and optimization prospects.

Oncolytic viruses (OVs) are emerging cancer therapeutics that offer a multifaceted therapeutic platform for the benefits of replicating and lysing tumor cells, being engineered to express transgenes, modulating the tumor microenvironment (TME), and having a tolerable safety profile that does not overlap with other cancer therapeutics. The mechanism of OVs combined with other antitumor agents is based on immune-mediated attack resistance and might benefit patients who fail to achieve durable responses after immune checkpoint inhibitor (ICI) treatment. In this Review, we summarize data on the OV mechanism and limitations of monotherapy, which are currently in the process of combination partner development, especially with ICIs. We discuss some of the hurdles that have limited the preclinical and clinical development of OVs. We also describe the available data and provide guidance for optimizing OVs in clinical practice, as well as a summary of approved and promising novel OVs with clinical indications.

Single cell sequencing revealed the mechanism of PD-1 resistance affected by the expression profile of peripheral blood immune cells in ESCC.

Background: Esophageal squamous carcinoma (ESCC) is a highly lethal malignancy with poor prognosis. The effect of transcriptome characteristics of patient immune microenvironment (TME) on the efficacy of immunosuppressive agents is still poorly understood. Methods: Here we extracted and isolated immune cells from peripheral blood of patients with PD-1 monoclonal antibody sensitivity and resistance, and conducted deep single-cell RNA sequencing to describe the baseline landscape of the composition, lineage, and functional status of infiltrating immune cells in peripheral blood of patients with esophageal cancer. Results: The transcriptome characteristics of immune cells were comprehensively analyzed, and the dynamic changes of cell percentage, heterogeneity of cell subtypes and interactions between cells were explained. Co-expression and pedigree tracking based on T-cell antigen receptors revealed a significant proportion of highly migratory intertissue-effector T cells. GO and KEGG enrichment pathway Analysis of CD8+ effect-T cells ESCC_S group and ESCC_D1,2 group, found that in the up-regulated enrichment pathway, ESCC_S group enriched more PD-L1 and PD-1 checkpoint pathways expressed in tumors (JUN/NFKBIA/FOS/KRAS/IFNG), which also exist in T cell receptor signaling pathways. MT2A, MT1X and MT1E were differentially expressed in ESCC patients with PD-1 monoclonal antibody resistance, which may be related to the resistance of PD-1 mMAB. Conclusions: This study has an in-depth understanding of the influence of peripheral immune cell infiltration on the sensitivity of monoclonal antibody PD-1 in patients with esophageal cancer, which is helpful to promote the immunotherapy of patients with esophageal cancer.

Identification of miR-135b as a novel regulator of TGFß pathway in gastric cancer.

Gastric cancer (GC) is a common malignant tumor worldwide, with a high incidence and low survival rate. The transforming growth factor-beta (TGFß) signaling pathway usually plays a tumor-suppressive role and is normally quietened in GC. The downregulation of transforming growth factor-beta receptor II (TGFBR2) affects TGFß signaling pathway, which exerts an immense effect on tumor cell proliferation and metastasis. Although the effect of the TGFß signaling pathway on cancer cells is well studied, little is known about the mechanism by which TGFBR2 expression is downregulated. Here, we showed that TGFBR2 protein, but not TGFBR2 mRNA, was consistently downregulated in GC, suggesting that post-transcriptional mechanism is involved in the regulation of TGFBR2. Bioinformatics analysis and luciferase reporter analysis proved that miR-135b combines precisely with the 3'-UTR of TGFBR2 mRNA. EdU assays and cell migration assays respectively showed that miR-135b overexpression induced the growth and invasion of GC cells. However, the overexpression of TGFBR2 had the opposite effect. TGFBR2 acted as the direct target for miR-135b and was downregulated in gastric cancer cells. Therefore, miR-135b promotes proliferation and migration of GC cells by negatively regulating TGFBR2 expression, displaying an oncomiR effect. Altogether, this conclusive evidence supported that miR-135b mediates the progression of GC by targeting TGFBR2 and miR-135b/TGFBR2 axis can be used in future targeted therapy for GC.