Electrophysiology of ionotropic GABA receptors.

GABAA receptors are ligand-gated chloride channels and ionotropic receptors of GABA, the main inhibitory neurotransmitter in vertebrates. In this review, we discuss the major and diverse roles GABAA receptors play in the regulation of neuronal communication and the functioning of the brain. GABAA receptors have complex electrophysiological properties that enable them to mediate different types of currents such as phasic and tonic inhibitory currents. Their activity is finely regulated by membrane voltage, phosphorylation and several ions. GABAA receptors are pentameric and are assembled from a diverse set of subunits. They are subdivided into numerous subtypes, which differ widely in expression patterns, distribution and electrical activity. Substantial variations in macroscopic neural behavior can emerge from minor differences in structure and molecular activity between subtypes. Therefore, the diversity of GABAA receptors widens the neuronal repertoire of responses to external signals and contributes to shaping the electrical activity of neurons and other cell types.

The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance.

Intratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land's cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5∆ClbQ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.

Main modulators of COVID-19 epidemic in sub-Saharan Africa.

Background: The coronavirus disease 2019 (COVID-19) pandemic is responsible for an important global death toll from which sub-Saharan Africa (SSA) seems mostly protected. The reasons explaining this situation are still poorly understood. Methods: We analyzed the correlation between reported COVID-19 data between February 14, 2020 and May 18, 2021, and demographic, socioeconomic, climatic, diagnostic data, and comorbidities in 47 SSA countries. Different databases including the WHO data center, Our World in Data, and the World Bank were used. Findings: As of May 17, 2021, SSA reported 2% of COVID-19 cases and 2.9% of deaths, with the southern region being the most affected with 56.4% of cases and 75.0% of deaths. COVID-19 mortality was positively correlated with medical variables (national obesity rate, diabetes prevalence, cancer incidence, and cardiovascular disease mortality rate), socioeconomic characteristics (international tourism, per capita health expenditure, human development index, HDI, and years of schooling), and health system variables (nurse density, number of COVID-19 tests per capita), but negatively correlated with the population under 15 years of age and the malaria index. Interpretation: Our study suggests that higher economic status fits with high COVID-19 mortality in SSA. In this regard, it represents primarily a disease of modern and wealthy societies, and can therefore be considered as an exception among infectious diseases that historically affected more severely underserved populations living in low- and middle-income countries. However, it should be made clear that observed correlations do not imply inevitably causation and that additional studies are necessary to confirm our observations.

Genomic Instability and Protumoral Inflammation Are Associated with Primary Resistance to Anti-PD-1 + Antiangiogenesis in Malignant Pleural Mesothelioma.

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas' primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti-PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology. SIGNIFICANCE: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti-PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799.

BCG therapy downregulates HLA-I on malignant cells to subvert antitumor immune responses in bladder cancer.

Patients with high-risk, nonmuscle-invasive bladder cancer (NMIBC) frequently relapse after standard intravesical bacillus Calmette-Guérin (BCG) therapy and may have a dismal outcome. The mechanisms of resistance to such immunotherapy remain poorly understood. Here, using cancer cell lines, freshly resected human bladder tumors, and samples from cohorts of patients with bladder cancer before and after BCG therapy, we demonstrate 2 distinct patterns of immune subversion upon BCG relapse. In the first pattern, intracellular BCG infection of cancer cells induced a posttranscriptional downregulation of HLA-I membrane expression via inhibition of autophagy flux. Patients with HLA-I-deficient cancer cells following BCG therapy had a myeloid immunosuppressive tumor microenvironment (TME) with epithelial-mesenchymal transition (EMT) characteristics and dismal outcomes. Conversely, patients with HLA-I-proficient cancer cells after BCG therapy presented with CD8+ T cell tumor infiltrates, upregulation of inflammatory cytokines, and immune checkpoint-inhibitory molecules. The latter patients had a very favorable outcome. We surmise that HLA-I expression in bladder cancers at relapse following BCG does not result from immunoediting but rather from an immune subversion process directly induced by BCG on cancer cells, which predicts a dismal prognosis. HLA-I scoring of cancer cells by IHC staining can be easily implemented by pathologists in routine practice to stratify future treatment strategies for patients with urothelial cancer.

Chemokine biology on immune checkpoint-targeted therapies.

The use of antagonistic immune checkpoint-targeted monoclonal antibodies has profoundly modified the standard of care and significantly increased the survival for many cancers. However, many patients still do not respond to those treatments. Biomarkers predictive for efficacy or failure of such immunotherapies would allow developing treatment stratification strategies which could further increase the survival rates of patients with cancer. Chemokines are a subset of the immune cell messenger molecules known as cytokines. Chemokines are key chemoattractant molecules which are essential for the homing of immune cells, notably within tumours. Therefore, they are good candidates for providing predictive biomarkers of the clinical response to checkpoint blockade immunotherapies. In this review, we summarise the recent advances in our understanding of the role of chemokines and how chemokine concentrations may set the tone for the efficacy of immune checkpoint-targeted immunotherapies.