The 9-1-1 Complex Controls Mre11 Nuclease and Checkpoint Activation during Short-Range Resection of DNA Double-Strand Breaks.

Summary Homologous recombination is initiated by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs). DSB resection is a two-step process in which an initial short-range step is catalyzed by the Mre11-Rad50-Xrs2 (MRX) complex and limited to the vicinity of the DSB end. Then the two long-range resection Exo1 and Dna2-Sgs1 nucleases extend the resected DNA tracts. How short-range resection is regulated and contributes to checkpoint activation remains to be determined. Here, we show that abrogation of long-range resection induces a checkpoint response that decreases DNA damage resistance. This checkpoint depends on the 9-1-1 complex, which recruits Dpb11 and Rad9 at damaged DNA. Furthermore, the 9-1-1 complex, independently of Dpb11 and Rad9, restricts short-range resection by negatively regulating Mre11 nuclease. We propose that 9-1-1, which is loaded at the leading edge of resection, plays a key function in regulating Mre11 nuclease and checkpoint activation once DSB resection is initiated

Immune Checkpoint Inhibitor Rechallenge and Resumption: a systematic review

Purpose of the review: The reintroduction of immune checkpoint inhibitors (ICIs) after disease progression (rechallenge) or immune-related adverse events (irAEs) recovering (resumption) raises questions in terms of efficacy and safety. Recent findings: Here, we reviewed literature data about ICIs rechallenge/resumption in cancer patients along with their clinical characteristics to explore those factors associated with better outcomes. Summary: Heterogenous results were pointed out across rechallenge studies with an overall response rate between 0% and 54%, a progression free survival ranged from 1,5 and 12,9 months and an overall survival between 6,5 and 23,8 months. Better outcomes have been recorded in patients with good ECOG PS, longer duration of initial ICI, discontinuation reason of initial ICI other than progression and those who received ICI sequence other than the switch between anti-PD1 and anti-PDL1. Studies about ICI resumption highlighted that certain types of irAEs were more likely to relapse at retreatment. These results suggest that ICI rechallenge / resumption can be an interesting strategy for selected patients

Local unwinding of double-strand DNA ends by the MRX complex promotes Exo1 processing activity

Homologous recombination is initiated by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs), which involves different nucleases including the Mre11-Rad50-Xrs2 (MRX) complex and the Exonuclease 1 (Exo1). The characterization of a novel mutation in Mre11 causing accelerated DSB resection has allowed to show that MRX facilitates DNA end processing by Exo1 through local unwinding of double-stranded DNA ends

Functions and regulation of the MRX complex at DNA double-strand breaks

DNA double-strand breaks (DSBs) pose a serious threat to genome stability and cell survival. Cells possess mechanisms that recognize DSBs and promote their repair through either homologous recombination (HR) or non-homologous end joining (NHEJ). The evolutionarily conserved Mre11-Rad50-Xrs2 (MRX) complex plays a central role in the cellular response to DSBs, as it is implicated in controlling end resection and in maintaining the DSB ends tethered to each other. Furthermore, it is responsible for DSB signaling by activating the checkpoint kinase Tel1 that, in turn, supports MRX function in a positive feedback loop. The present review focuses mainly on recent works in the budding yeast Saccharomyces cerevisiae to highlight structure and regulation of MRX as well as its interplays with Tel1

Human Tumor-Infiltrating Dendritic Cells: From In Situ Visualization to High-Dimensional Analyses

The interaction between tumor cells and the immune system is considered to be a dynamic process. Dendritic cells (DCs) play a pivotal role in anti-tumor immunity owing to their outstanding T cell activation ability. Their functions and activities are broad ranged, triggering different mechanisms and responses to the DC subset. Several studies identified in situ human tumor-infiltrating DCs by immunostaining using a limited number of markers. However, considering the heterogeneity of DC subsets, the identification of each subtype present in the immune infiltrate is essential. To achieve this, studies initially relied on flow cytometry analyses to provide a precise characterization of tumor-associated DC subsets based on a combination of multiple markers. The concomitant development of advanced technologies, such as mass cytometry or complete transcriptome sequencing of a cell population or at a single cell level, has provided further details on previously identified populations, has unveiled previously unknown populations, and has finally led to the standardization of the DCs classification across tissues and species. Here, we review the evolution of tumor-associated DC description, from in situ visualization to their characterization with high-dimensional technologies, and the clinical use of these findings specifically focusing on the prognostic impact of DCs in cancers

Advances and Therapeutic Perspectives in Extended-Stage Small-Cell Lung Cancer

Extended small cell lung cancer (ED-SCLC) is a very aggressive disease, characterized by rapid growth and an early tendency to relapse. In contrast to non-small cell lung cancer, no therapeutic innovation has improved survival in patients with ED-SCLC over the past 20 years. Recently, immunotherapy has shown an important role in the management of these patients, emerging as the treatment of first choice in combination with chemotherapy and completely changing the therapeutic paradigm. However, patients’ selection for this strategy is still challenging due to a lack of reliable predictive biomarkers. Conversely, the immunotherapy efficacy beyond the first line is pretty disappointing and innovative chemotherapies or target agents seem to be more promising in this setting. Some of them are also under evaluation as an upfront strategy and they will probably change the treatment algorithm in the next future. This proposal provides a comprehensive overview of available treatment strategies for ED-SCLC patients, highlighting their strengths and weaknesses