Liwen Zhang

Identification of m7G Methylation‐Related miRNA Signature Associated with Survival and Immune Microenvironment Regulation in Uterine Corpus Endometrial Carcinoma

Background. N7‐methylguanosine (m7G) has been implicated in the development of cancer. The role of m7G‐related miRNAs in the survival prediction of UCEC patients has not been investigated. Current research was the first to construct an m7G‐related miRNA model to accurately predict the survival of patients with uterine corpus endometrial carcinoma (UCEC) and to explore immune cell infiltration and immune activity in the tumor microenvironment. Methods. RNA‐seq data and clinical information of UCEC patients were derived from The Cancer Genome Atlas (TCGA) database. Using the TargetScan online database, we predicted miRNAs linked to the m7G‐related genes and identified miRNAs which were significantly associated with the survival in UCEC patients and constructed a risk scoring model. The TCGA‐UCEC cases were scored according to the risk model, and the high‐ and low‐risk groups were divided by the median risk value. Gene enrichment analysis and immune cell infiltration and immune function analysis were performed using “clusterProfiler” and “GSVA” packages in R. Results. The survival prediction model consisted of 9 miRNAs, namely, hsa‐miR‐1301, hsa‐miR‐940, hsa‐miR‐592, hsa‐miR‐3170, hsa‐miR‐876, hsa‐miR‐215, hsa‐miR‐934, hsa‐miR‐3920, and hsa‐miR‐216b. Survival of UCEC patients in the high‐risk group was worse than that in the low‐risk group (p < 0.001). The receiver operating characteristic (ROC) curve showed that the model had good predictive performance, and the area under the curve was 0.800, 0.690, and 0.705 for 1‐, 3‐, and 5‐year survival predictions, respectively. There were differences in the degree of immune cell infiltration and immune activity between the low‐risk and high‐risk groups. The expression levels of the identified differentially expressed genes correlated with the susceptibility to multiple anticancer drugs. Conclusions. The survival prediction model constructed based on 9 m7G‐related miRNAs had good predictive performance.

Ligand-based adoptive T cell targeting CA125 in ovarian cancer

Abstract Background Ovarian cancer (OC) is a highly aggressive gynecological malignancy prevalent worldwide. Most OC cases are typically diagnosed at advanced stages, which has led to a 5-year overall survival rate of less than 35% following conventional treatment. Furthermore, immune checkpoint inhibitor therapy has shown limited efficacy in the treatment of patients with OC, and CAR-T therapy has also demonstrated modest results owing to inadequate T cell infiltration. Therefore, novel strategies must be developed to enhance T cell persistence and trafficking within the OC tumor microenvironment. Methods In this study, we developed a novel adoptive T-cell therapy for ovarian cancer based on a chimeric antigen receptor structure. We used a ligand-receptor binding motif to enhance the therapeutic effect of targeting CA125. Since mesothelin can naturally bind to CA125 with high affinity, we concatenated the core-binding fragment of mesothelin with the 4-1BB and CD3ζ signal fragments to assemble a novel CA125-targeting chimeric receptor (CR). The CAR structure targeting CA125 derived from the 4H11 antibody was also constructed. CR- and CAR-encoding RNA were electroporated into T cells to evaluate their antitumor activity both in vitro and in vivo. Results While CR-T or CAR-T cells exhibited moderate activity against two ovarian cancer cell lines, T cells co-expressing CR and CAR exhibited a superior killing effect compared to T cells expressing either CR or CAR alone. Furthermore, upon interaction with ovarian tumors, the ability of CR and CAR T cells to release activation markers and functional cytokines increased significantly. Similarly, CR and CAR co-expressing T cells persistently controlled the growth of transplanted ovarian cancer tumors in NSG mice and significantly prolonged the overall survival of tumor-challenged mice. Transcriptome sequencing revealed that the survival and cytotoxicity of T cells co-expressing CR and CAR were significantly altered compared with those of T cells expressing either CR or CAR. Conclusion Our findings demonstrate that CA125 targeting CR and CAR can synergistically kill ovarian cancer cells, indicating that CA125 targeting by the two binding motifs simultaneously in tumors may improve the therapeutic outcomes of ovarian cancer treatment.

Development of a deep learning‐based nomogram for predicting lymph node metastasis in cervical cancer: A multicenter study