Exosome-based anticancer vaccines: From Bench to bedside.

Exosomes, a subset of extracellular vesicles, are released by all active cells and play a crucial role in intercellular communications. Exosomes could facilitate the transfer of various biologically active molecules, such as DNA, non-coding RNAs, and proteins, from donor to recipient cells, thereby participating in diverse biological and pathological processes. Besides, exosomes possess unique characteristics, including non-toxicity, low-immunogenicity, and stability within biological systems, rendering them highly advantageous for cancer drug development. Meanwhile, accumulating evidence suggests that exosomes originating from tumor cells and immune cells possess distinct composition profiles that play a direct role in anticancer immunotherapy. Of note, exosomes can transport their contents to specific cells, thereby exerting an impact on the phenotype and immune-regulatory functions of targeted cells. Therapeutic cancer vaccines, an emerging therapeutics of immunotherapy, could enhance antitumor immune responses by delivering a large number of tumor antigens, thereby augmenting the immune response against tumor cells. Therefore, the therapeutic rationale of cancer vaccines and exosome-based immunotherapy are almost similar to some extent, but some challenges have hindered their application in the clinical setting. Here, in this review, we first summarized the biogenesis, structure, compositions, and biological functions of exosomes. Then we described the roles of exosomes in cancer biology, particularly in tumor immunity. We also comprehensively reviewed current exosome-based anticancer vaccine development and we divided them into three types. Finally, we give some insights into clinical translation and clinical trial progress of exosome-based anticancer vaccines for future direction.

Genetically predicted blood metabolites mediate the association between circulating immune cells and pancreatic cancer: A Mendelian randomization study.

BACKGROUND: Pancreatic cancer is characterized by metabolic dysregulation and unique immunological profiles. Nevertheless, the comprehensive understanding of immune and metabolic dysregulation of pancreatic cancer remains unclear. In the present study, we aimed to investigate the causal relationship of circulating immune cells and pancreatic cancer and identify the blood metabolites as potential mediators. METHODS: The exposure and outcome genome-wide association studies (GWAS) data used in the present study were obtained from the GWAS open-access database (https://gwas.mrcieu.ac.uk). The study used 731 circulating immune cell features, 1400 types of blood metabolites and pancreatic cancer from GWAS. We then performed bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between the circulating immune cells and pancreatic cancer, and two-step MR to discover potential mediating blood metabolites in this process. All statistical analyses were performed in R software. The STROBE-MR (i.e. Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization) checklist for the reporting of MR studies was also used. RESULTS: MR analysis identified seven types of circulating immune cells causally associated with pancreatic cancer. Furthermore, there was no strong evidence that genetically predicted pancreatic cancer had an effect on these seven types of circulating immune cells. Further two-step MR analysis found 10 types of blood metabolites were causally associated with pancreatic cancer and the associations between circulating CD39+CD8+ T cells and pancreatic cancer were mediated by blood orotates with proportions of 5.18% (p = 0.016). CONCLUSIONS: The present study provides evidence supporting the causal relationships between various circulating immune cells, especially CD39+CD8+ T cells, and pancreatic cancer, with a potential effect mediated by blood orotates. Further research is needed on additional risk factors as potential mediators and establish a comprehensive immunity-metabolism network in pancreatic cancer.

Small airway dysfunction associated with poor short-term outcomes in patients undergoing thoracoscopic surgery for lung cancer.

BACKGROUND: Although small airway dysfunction is a common respiratory dysfunction, its prognosis after lung cancer surgery is often neglected. This study investigated the relationship between small airway dysfunction and outcomes in patients who underwent thoracoscopic surgery for lung cancer. METHODS: A retrospective cohort study of patients who underwent thoracoscopic surgery was conducted between December 2019 and March 2021 at Ningbo First Hospital. We used univariate and multivariate analyses to assess the possible associations between postoperative outcomes and clinical variables, including small airway dysfunction. To balance the potential confounding factors, propensity score matching was performed to establish 1:1 small airway dysfunction and small airway normal function group matching. RESULTS: In this study, 1,012 patients undergoing thoracoscopic surgery for lung cancer were enrolled. Small airway dysfunction was present in 18.7% of patients (189/1,012). The incidence of postoperative pulmonary complications in the small airway dysfunction group was higher than that of the small airway normal function group (16.4% vs 6.2%, P < .001). The most significant postoperative pulmonary complications were pneumonia (7.4% vs 2.4%, P < .001) in the small airway dysfunction and normal function groups, respectively. In addition, a significantly prolonged median hospital length of stay was observed in the small airway dysfunction group compared to the small airway normal function group (median [interquartile range], 9 [7-12] vs 8 [7-9], P < .001). After 1:1 propensity score matching, 298 patients (149 pairs) were included in the comparison between small airway dysfunction and small airway normal function, and this association remained. Postoperative pulmonary complications (13.4% vs 6.0%, P = .032) were still higher, and length of stay (median [interquartile range] 9 [7-11] vs 8 [6-10] days, P = .001) was still longer in the small airway dysfunction group. Multivariate analysis indicated that small airway dysfunction was the independent risk factor associated with both postoperative pulmonary complications (odds ratio = 2.694, 95% confidence interval: 1.640-4.426, P < .001) and prolonged length of stay (beta = 1.045, standard error = 0.159, 95% confidence interval: 0.733-1.357, P < .001). CONCLUSION: Our study showed that small airway dysfunction increased the incidence of postoperative pulmonary complications and prolonged length of stay in patients undergoing thoracoscopic surgery for lung cancer.

Whole Blood-Derived circUSP10 Acts as a Diagnostic Biomarker in Patients With Early-Stage Non-Small-Cell Lung Cancer.

Accumulating evidence has indicated that differentially expressed noncoding circular RNAs (circRNAs) play essential roles in the occurrence and development of various types of cancer. Here, we aimed to identify and explore the diagnostic value of hsa_circ_0003026 (named circUSP10) in patients with early non-small-cell lung cancer (NSCLC). The differentially expressed circRNAs were screened from the microarray-based assay of human NSCLC tissues and their corresponding noncancerous tissues, and the candidate circRNAs were further verified in patients with NSCLC using reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Circulating circUSP10 was isolated from whole blood of healthy people and patients with NSCLC and was detected by RT-qPCR. In addition, the diagnostic value of circUSP10 in early NSCLC was evaluated by receiver operating characteristic (ROC) curve analysis. We found that circUSP10 was upregulated in tumor tissues from patients with early NSCLC and associated with tumor size and tumor-node-metastasis (TNM) stage. Importantly, circUSP10 was obviously upregulated in the whole blood of patients with NSCLC. Additionally, whole blood-derived circUSP10 showed good diagnostic performance for screening early NSCLC and was relatively stable in blood under adverse conditions. These findings demonstrate that circUSP10 may act as a novel biomarker for the diagnosis of early-stage NSCLC, suggesting the potential of circUSP10 in RNA-based therapy for cancer.

Peripheral Blood-Derived CircVPS35L as a Potential Diagnostic Biomarker for Non-Small Cell Lung Cancer.

INTRODUCTION: Circular RNAs (circRNAs) are dysregulated in cancers and are stably expressed in body fluids such as blood. We therefore identified and evaluated the clinical value of a newly found circRNA VPS35L (circVPS35L) as a biomarker for the diagnosis of non-small cell lung cancer (NSCLC). METHODS: Reverse-transcription quantitative PCR (RT-qPCR) was used to determine the expression levels of circVPS35L in tissues, whole blood, and cell lines. The actinomycin D assay and RNase R treatment were utilized to determine the stability of circVPS35L. Receiver operating characteristic (ROC) curve analysis was conducted to predict the diagnostic value of blood-derived circVPS35L in NSCLC. RESULTS: CircVPS35L was found to be downregulated in NSCLC tissues and cell lines. Interestingly, circVPS35L expression was significantly correlated with tumor size (p = 0.0269), histology type (p < 0.0001), and TNM stage (p = 0.0437). Importantly, circVPS35L was poorly expressed in peripheral blood of NSCLC patients when compared with healthy controls and patients with benign lung disease. ROC analysis revealed a higher diagnostic value of circVPS35L than the three conventional tumor markers (CYFR21-1, NSE, and CEA) in patients with NSCLC. Moreover, circVPS35L was highly stable in peripheral blood when exposed to undesirable conditions. CONCLUSION: These findings demonstrate that circVPS35L has great potential as a novel biomarker for the diagnosis of NSCLC and can be used to distinguish NSCLC from benign lung disease.

MicroRNA-490-3p and -490-5p in carcinogenesis: Separate or the same goal?

MicroRNA (miR)-490-3p and miR-490-5p, located on chromosome 7q33, are two independent mature products of miR-490 exerting distinct effects on tumor progression. miR-490-3p and miR-490-5p possess antitumor properties. miR-490-3p dysfunction has been associated with malignancies including colorectal cancer, while the abnormal function of miR-490-5p has been more considerably associated with bladder cancer (for example). At present, there are 30 and 11 target genes of miR-490-3p and miR-490-5p, respectively, that have been experimentally verified, of which the cyclin D1 (CCND1) gene is a common target. Through these target genes, miR-490-3p and miR-490-5p are involved in 7 and 3 signaling pathways, respectively, of which only 2 are shared regulatory signaling pathways. The present review introduces two competing endogenous RNA (ceRNA) regulatory networks centered on miR-490-3p and miR-490-5p. These networks may be important promoters of tumor cell proliferation, invasiveness, metastatic potential and apoptosis. Unlike miR-490-5p, miR-490-3p plays a unique role in promoting cancer. However, both are promising molecular markers for early cancer diagnosis and prognosis. In addition, miR-490-3p was also found to be associated with the chemical resistance of cisplatin and paclitaxel. The present review focuses on the abnormal expression of miR-490-3p and miR-490-5p in different tumor types, and their complex ceRNA regulatory networks. The clinical value of miR-490-3p and miR-490-5p in cancer diagnosis, prognosis and treatment is also clarified, and an explanation for the opposing effects of miR-490-3p in tumor research is provided.