Emerging Role of Circulating Tumor Cells in Gastric Cancer

With over 1 million incidence cases and more than 780,000 deaths in 2018, gastric cancer (GC) was ranked as the 5th most common cancer and the 3rd leading cause of cancer deaths worldwide. Though several biomarkers, including carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), and cancer antigen 72-4 (CA72-4), have been identified, their diagnostic accuracies were modest. Circulating tumor cells (CTCs), cells derived from tumors and present in body fluids, have recently emerged as promising biomarkers, diagnostically and prognostically, of cancers, including GC. In this review, we present the landscape of CTCs from migration, to the presence in circulation, biologic properties, and morphologic heterogeneities. We evaluated clinical implications of CTCs in GC patients, including diagnosis, prognosis, and therapeutic management, as well as their application in immunotherapy. On the one hand, major challenges in using CTCs in GC were analyzed, from the differences of cut-off values of CTC positivity, to techniques used for sampling, storage conditions, and CTC molecular markers, as well as the unavailability of relevant enrichment and detection techniques. On the other hand, we discussed future perspectives of using CTCs in GC management and research, including the use of circulating tumor microembolies; of CTC checkpoint blockade in immunotherapy; and of organoid models. Despite the fact that there are remaining challenges in techniques, CTCs have potential as novel biomarkers and/or a non-invasive method for diagnostics, prognostics, and treatment monitoring of GC, particularly in the era of precision medicine

Metabolic Dysregulation Induces Impaired Memory Lymphocyte Formation During Severe SARS-COV-2 Infection

Metabolic dysregulation accompanying SARS-CoV-2 infection is a key determinant of disease severity. In this study, we performed extensive data mining of multiple existing single-cell RNA seq datasets of COVID-19 BALFs, in combination with high-dimensional immune cell profiling of PBMCs from COVID-19-infected patients, to get a comprehensive, systemic profile of the immunometabolic regulation of adaptive immunity during severe COVID-19. Hypoxia, a hallmark of COVID-19 ARDS, was found to elicit a global metabolic reprogramming in effector lymphocytes. In response to oxygen and nutrient-deprived microenvironments, these cells shift from aerobic respiration to increase their dependence on anaerobic processes including glycolysis, mitophagy, and glutaminolysis to fulfill their bioenergetic demands. We find that these metabolically reprogrammed CD8 and NK cells, under persistent antigen stimulation, become exhausted, displaying impaired cytotoxic function and anti-viral efficacy. We demonstrate that dysregulated metabolism significantly impairs memory lymphocyte differentiation, including the formation of memory NK and tissue resident CD8 memory cells. Unsupervised clustering techniques revealed multiple distinct, differentially abundant CD8 and NK memory cell states that are marked by high glycolytic flux, mitochondrial dysfunction, and cellular exhaustion, further highlighting the connection between disrupted metabolism and impaired memory cell function in COVID-19. Overall, our findings provide novel insight on how SARS-CoV-2 infection affects host immunometabolism and anti-viral response during COVID-19

Metabolic dysregulation impairs lymphocyte function during severe SARS-CoV-2 infection

Mitophagy inhibition rescues cellular dysfunction through enhancing metabolic fitness in CD8 and NKT lymphocytes during SARS-CoV-2 infection