Expression of circular RNAs in myelodysplastic neoplasms and their association with mutations in the splicing factor gene SF3B1.

Mutations in the splicing factor 3b subunit 1 (SF3B1) gene are frequent in myelodysplastic neoplasms (MDS). Because the splicing process is involved in the production of circular RNAs (circRNAs), we investigated the impact of SF3B1 mutations on circRNA processing. Using RNA sequencing, we measured circRNA expression in CD34+ bone marrow MDS cells. We defined circRNAs deregulated in a heterogeneous group of MDS patients and described increased circRNA formation in higher-risk MDS. We showed that the presence of SF3B1 mutations did not affect the global production of circRNAs; however, deregulation of specific circRNAs was observed. Particularly, we demonstrated that strong upregulation of circRNAs processed from the zinc finger E-box binding homeobox 1 (ZEB1) transcription factor; this upregulation was exclusive to SF3B1-mutated patients and was not observed in those with mutations in other splicing factors or other recurrently mutated genes, or with other clinical variables. Furthermore, we focused on the most upregulated ZEB1-circRNA, hsa_circ_0000228, and, by its knockdown, we demonstrated that its expression is related to mitochondrial activity. Using microRNA analyses, we proposed miR-1248 as a direct target of hsa_circ_0000228. To conclude, we demonstrated that mutated SF3B1 leads to deregulation of ZEB1-circRNAs, potentially contributing to the defects in mitochondrial metabolism observed in SF3B1-mutated MDS.

Lactate from the tumor microenvironment - A key obstacle in NK cell-based immunotherapies.

Recent findings about the new roles of lactate have changed our understanding of this end product of glycolysis or fermentation that was once considered only a waste product. It is now well accepted that lactate acts as a signaling molecule and fuel source for cancer cells in a glucose-restricted environment. Moreover, lactate and lactate dehydrogenase are markers of poor prognosis of many cancers and regulate many functions of immune cells. The presence of lactate in the tumor microenvironment (TME) leads to polarization of the immunosuppressive phenotypes of dendritic cells and impairs the cytotoxic abilities of T cells and NK cells, and as such lactate is a major obstacle to immune-cell effector functions and the efficacy of cell-based immunotherapies. Emerging evidence suggests that lactate in the TME might be a novel therapeutic target to enhance the immunotherapeutic potential of cell-based therapies. This review describes our current understanding of the role of lactate in tumor biology, including its detrimental effects on cell-based immunotherapy in cancer. We also highlight how the role of lactate in the TME must be considered when producing cell therapies designed for adoptive transfer and describe how targeted modulation of lactate in the TME might boost immune-cell functions and positively impact cellular immunotherapy, with a focus on NK cell.