Background: Tumor mutational burden (TMB) is a genomic biomarker that can predict favorable responses to immune checkpoint inhibitors (ICIs). Although we have better understanding of TMB in cancer immunity and cancer immunotherapy, the relationship between TMB and the clinical efficacy of ICIs remains unknown in the treatment of melanoma patients. Here, we conduct a systematic review and meta-analysis to evaluate the predictive value of TMB on the efficacy of ICIs in patients with melanoma.Methods: We systematically collected data from PubMed, Embase, Cochrane Library, CNKI, China Biomedical Database (CBM), and Wanfang Database. The end date was set to 26 June 2021. We included retrospective studies or clinical trials of ICIs that reported hazard ratios (HRs) for overall survival and/or progression-free survival according to TMB. Data for 1,493 patients from 15 studies were included. In addition, pooled effect size, heterogeneity analysis, sensitivity analysis, publication bias detection, and subgroup analysis were performed based on the included data.Results: Patients with high TMB showed significantly improved OS (HR = 0.49, 95% CI: 0.33, 0.73; p = 0.001) and PFS (HR = 0.47, 95% CI: 0.33, 0.68; p < 0.001) compared with patients with low TMB. This association was very good in patients treated with monotherapy, that is, anti-CTLA-4 or anti-PD-(L)-1 inhibitors, but not for the patients treated with a combination of the two drugs. The subgroup analysis results showed that heterogeneity was substantial in the targeted next-generation sequencing (NGS) group. Publication bias was detected, and the results were visualized using the funnel chart. And sensitivity analysis and trim-and-fill method analysis showed that our results were stable and reliable.Conclusion: High TMB is associated with improved OS and PFS in melanoma patients treated with mono-drug ICIs. TMB determined by NGS should be standardized to eliminate heterogeneity. Therefore, the role of TMB in identifying melanoma patients who may benefit from ICI should be further determined in more randomized controlled trials in the future.

Advances in the understanding of psychoneuroimmunology in the past decade have emphasized the notion that stress and cancer are interlinked closely. Durable chronic stress accelerated tumorigenesis and progression, which is unfavorable for clinical outcomes of cancer patients. Available evidence has provided unprecedented knowledge about the role and mechanisms of chronic stress in carcinogenesis, the most well-known one is dysfunction of the hypothalamus-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). With abnormal activation of neuroendocrine system, stress-related hormones contribute to increased oncogenes expression, exacerbated chronic inflammation and impaired immunologic function. In addition, accumulating studies have demonstrated that diverse stress interventions including pharmacological approaches, physical exercises and psychological relaxation have been administered to assist in mental disorders reduction and life quality improvement in cancer patients. In this review, we systematically summarize the connection and mechanisms in the stress-immune-cancer axis identified by animal and clinical studies, as well as conclude the effectiveness and deficiencies of existing stress management strategies.

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Background Osteosarcoma (OS) is the most frequent cancer derived from bone, and the prognosis of OS is poor. Metabolic alterations have been previously reported to contribute to the development of OS, and arsenic compounds have been suggested to exhibit strong anti-OS effects. However, few studies have described the therapeutic efficiency of arsenic compounds by targeting metabolism in OS. Methods Here, we presented a novel organo-arsenic compound, Aa-Z2, and its antitumour efficacy against OS both in vitro and in vivo. Results Aa-Z2 induced OS cell apoptosis, G2/M phase arrest, and autophagy through the accumulation of reactive oxygen species (ROS). Elevated ROS functioned by promoting the mitochondrial-dependent caspase cascade and attenuating the PI3K/Akt/mTOR signalling pathway. N-acetylcysteine (NAC), a kind of ROS scavenger, could reverse the effects of Aa-Z2 treatment on 143B and HOS cells. Specifically, by targeting pyruvate dehydrogenase kinase 1 (PDK-1), Aa-Z2 induced changes in mitochondrial membrane potential and alterations in glucose metabolism to accumulate ROS. Overexpression of PDK-1 could partially desensitize OS cells to Aa-Z2 treatment. Importantly, Aa-Z2 suppressed tumour growth in our xenograft osteosarcoma model. Conclusion The study provides new insights into the mechanism of Aa-Z2-related metabolic alterations in OS inhibition, as well as pharmacologic evidence supporting the development of metabolism-targeting therapeutics.

Background Osteosarcoma is the most frequent primary bone malignancy with a poor prognosis because of pulmonary metastasis. Autophagy is strongly associated with tumor metastasis, and it is valuable to construct an autophagy-related gene risk model for predicting the prognosis of osteosarcoma. Methods We obtained ARGs from the Human Autophagy Database and RNA-sequencing data of osteosarcoma patients from the Gene Expression Omnibus (GEO) database. Subsequently, univariate and multivariate cox regression analyses were performed to construct a three-gene prognostic model and its accuracy was further confirmed in the Therapeutic Applications Research to Generate Effective Treatments (TARGET) database. Afterward, we detected the expression levels and effects on osteosarcoma cells metastasis of MYC and MBTPS2, which were involved in the model. Results In both training and verification cohorts, patients with lower risk scores had longer OS, and the model was identified as an independent prognostic factor in osteosarcoma. Besides, the ROC curve demonstrated the reliability of the model. Furthermore, RT-qPCR, Western Blotting and IHC results indicated that MYC and MBTPS2 were differently expressed in osteosarcoma tissues and cell lines. MYC knockdown or MBTPS2 overexpression prevented the capacity of migration and invasion in osteosarcoma cell lines through inhibiting cellular autophagy. Conclusion The risk model based on three ARGs had a strong ability to predict the prognosis of osteosarcoma patients. Our findings also suggested that MYC and MBTPS2 were two major factors regulating autophagy in osteosarcoma, and could serve as potential therapeutic targets for osteosarcoma.

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Background: In various malignant tumors, whether tumor mutational burden (TMB) was related to improving survival outcomes or promoting immunotherapy remained controversial. We aimed to study the prognosis of tumor mutation burden in cervical squamous cell carcinoma (CSCC) and its potential association with tumor-infiltrating immune cells.Methods: Transcriptome and somatic mutation profiles of CSCC were downloaded from the TCGA database. Somatic mutations were analyzed by "maftools" and visualized in waterfall plot. Then, TMB was calculated and we classified the samples into high-TMB and low-TMB groups based on the median data. Survival analysis and Wilcoxon test were used to investigate the prognostic value of TMB and its association with clinical variables. Differentially expressed genes (DEG) were identified in 2 TMN groups, and functional analysis was performed to find out significant biological pathways. Finally, we used the CIBERSORT algorithm to estimate the association between TMB and immune infiltration, and used the R package "vioplot" to visually draw the violin chart for each immune cell. Results: The data from TCGA were analyzed, and higher TMB levels conferred high overall survival time, associated with higher T staging (p = 0.048) and older age (p = 0.029). Then, the differential analysis determined 122 DEGs. And pathway research showed that the enrichment of TMB-related signature correlated with several cancer-related signaling pathways, including PI3K-Akt signaling pathway, Rap1 signaling pathway, MAPK signaling pathway and Ras signaling pathway. Through CIBERSORT package and Wilcoxon rank-sum test, T cells CD8 (p = 0.008), T cells CD4 memory activation (p = 0.002) and T cells follicular helper cells (p = 0.028) showed higher levels of infiltration in the high TMB group. However, T cells CD4 memory resting (p = 0.003) and T cells regulation (Tregs) (p = 0.033) showed lower levels of infiltration in the high TMB group. Conclusions: In summary, high TMB may inhibit the development of CSCC through anti-tumor immune cells. And our study might have some merits in elucidating the potential mechanism of TMB and immune infiltrates in CSCC and providing guidance of immunotherapy for endometrial cancer.