Sensitizing cancer cells to immune checkpoint inhibitors by microbiota-mediated upregulation of HLA class I.

Recent data have shown that gut microbiota has a major impact on the clinical response to immune checkpoint inhibitors (ICIs) in the context of solid tumors. ICI-based therapy acts by unlocking cognate cytotoxic T lymphocyte (CTL) effector responses, and increased sensitivity to ICIs is due to an enhancement of patients' tumor antigen (TA)-specific CTL responses. Cancer clearance by TA-specific CTL requires expression of relevant TAs on cancer cells' HLA class I molecules, and reduced HLA class I expression is a common mechanism used by cancer cells to evade the immune system. Here, we show that metabolites released by bacteria, in particular, phytosphingosine, can upregulate HLA class I expression on cancer cells, sensitizing them to TA-specific CTL lysis in vitro and in vivo, in combination with immunotherapy. This effect is mediated by postbiotic-induced upregulation of NLRC5 in response to upstream MYD88-NF-κB activation, thus significantly controlling tumor growth.

Gut vascular barrier impairment leads to intestinal bacteria dissemination and colorectal cancer metastasis to liver.

Metastasis is facilitated by the formation of a "premetastatic niche," which is fostered by primary tumor-derived factors. Colorectal cancer (CRC) metastasizes mainly to the liver. We show that the premetastatic niche in the liver is induced by bacteria dissemination from primary CRC. We report that tumor-resident bacteria Escherichia coli disrupt the gut vascular barrier (GVB), an anatomical structure controlling bacterial dissemination along the gut-liver axis, depending on the virulence regulator VirF. Upon GVB impairment, bacteria disseminate to the liver, boost the formation of a premetastatic niche, and favor the recruitment of metastatic cells. In training and validation cohorts of CRC patients, we find that the increased levels of PV-1, a marker of impaired GVB, is associated with liver bacteria dissemination and metachronous distant metastases. Thus, PV-1 is a prognostic marker for CRC distant recurrence and vascular impairment, leading to liver metastases.

Type III interferons disrupt the lung epithelial barrier upon viral recognition.

Viral infections of the lower respiratory tract are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. In this study, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report that IFN-λ is present in the lower, but not upper, airways of patients with coronavirus disease 2019 (COVID-19). In mice, we demonstrate that IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in clinical practice against endemic viruses, such as influenza virus as well as the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Early hemodynamic and biochemical changes in overloaded swine ventricle.

The present study was undertaken to investigate, in an animal model, the relationship between sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity, phospholamban phosphorylation, acylphosphatase activity, and hemodynamic changes that occur in the early phase of pressure overload. In 54 study-group pigs, weighing 40±5 kg each, an aortic stenosis was created with a band of umbilical tape tied around the aorta; 18 sham-operated pigs formed our control group. Eight animals (6 study and 2 control) were randomly assigned to each experimental time (0.5, 3, 6, 12, 24, 48, 72, 96, and 168 hr). All indices of left ventricular function declined significantly, with a peak at 6 hr and a return to baseline at 168 hr. At each observational time, SERCA2a activity, Ca2+ uptake, and acylphosphatase activity rose significantly, with a maximum increase at 6 hr. These changes indicated a higher expression of these proteins; conversely, phospholamban did not show significant changes in its concentration or in its phosphorylation status. Nuclear proto-oncogene c-fos expression rose at 6 hr. A strong inverse correlation was found when Ca2+-ATPase activity, Ca2+-ATPase expression, Ca2+ uptake, and acylphosphatase were compared with indices of systolic function. In our model of induced pressure overload, an initial phase of depressed myocardial contractility was accompanied by an increased sarcoplasmic reticulum function and by higher Ca2+-ATPase and Ca2+ uptake activities mediated by acylphosphatase. This new finding of Ca2+ homeostasis might indicate a compensatory mechanism for mechanical stress. Further studies are needed to confirm our findings.