Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Early attentional processes distinguish selective from global motor inhibitory control: An electrical neuroimaging study

The rapid stopping of specific parts of movements is frequently required in daily life. Yet, whether selective inhibitory control of movements is mediated by a specific neural pathway or by the combination between a global stopping of all ongoing motor activity followed by the re-initiation of task-relevant movements remains unclear. To address this question, we applied time-wise statistical analyses of the topography, global field power and electrical sources of the event-related potentials to the global vs selective inhibition stimuli presented during a Go/NoGo task. Participants (n = 18) had to respond as fast as possible with their two hands to Go stimuli and to withhold the response from the two hands (global inhibition condition, GNG) or from only one hand (selective inhibition condition, SNG) when specific NoGo stimuli were presented. Behaviorally, we replicated previous evidence for slower response times in the SNG than in the Go condition. Electrophysiologically, there were two distinct phases of event-related potentials modulations between the GNG and the SNG conditions. At 110–150 ms post-stimulus onset, there was a difference in the strength of the electric field without concomitant topographic modulation, indicating the differential engagement of statistically indistinguishable configurations of neural generators for selective and global inhibitory control. At 150–200 ms, there was topographic modulation, indicating the engagement of distinct brain networks. Source estimations localized these effects within bilateral temporo-parieto-occipital and within parieto-central networks, respectively. Our results suggest that while both types of motor inhibitory control depend on global stopping mechanisms, selective and global inhibition still differ quantitatively at early attention-related processing phases

Training-induced behavioral and brain plasticity in inhibitory control

Deficits in inhibitory control, the ability to suppress ongoing or planned motor or cognitive processes, contribute to many psychiatric and neurological disorders. The rehabilitation of inhibition-related disorders may therefore benefit from neuroplasticity-based training protocols aiming at normalizing inhibitory control proficiency and the underlying brain networks. Current literature on training-induced behavioral and brain plasticity in inhibitory control suggests that improvements may follow either from the development of automatic forms of inhibition or from the strengthening of top-down, controlled inhibition. Automatic inhibition develops in conditions of consistent and repeated associations between inhibition-triggering stimuli and stopping goals. Once established, the stop signals directly elicit inhibition, thereby bypassing slow, top-down executive control and accelerating stopping processes. In contrast, training regimens involving varying stimulus-response associations or frequent inhibition failures prevent the development of automatic inhibition and thus strengthen top-down inhibitory processes rather than bottom-up ones. We discuss these findings in terms of developing optimal inhibitory control training regimens for rehabilitation purposes

Differential patterns of functional and structural plasticity within and between inferior frontal gyri support training-induced improvements in inhibitory control proficiency

Ample evidence indicates that inhibitory control (IC), a key executive component referring to the ability to suppress cognitive or motor processes, relies on a right-lateralized fronto-basal brain network. However, whether and how IC can be improved with training and the underlying neuroplastic mechanisms remains largely unresolved. We used functional and structural magnetic resonance imaging to measure the effects of 2 weeks of training with a Go/NoGo task specifically designed to improve frontal top-down IC mechanisms. The training-induced behavioral improvements were accompanied by a decrease in neural activity to inhibition trials within the right pars opercularis and triangularis, and in the left pars orbitalis of the inferior frontal gyri. Analyses of changes in brain anatomy induced by the IC training revealed increases in grey matter volume in the right pars orbitalis and modulations of white matter microstructure in the right pars triangularis. The task-specificity of the effects of training was confirmed by an absence of change in neural activity to a control working memory task. Our combined anatomical and functional findings indicate that differential patterns of functional and structural plasticity between and within inferior frontal gyri enhanced the speed of top-down inhibition processes and in turn IC proficiency. The results suggest that training-based interventions might help overcoming the anatomic and functional deficits of inferior frontal gyri manifesting in inhibition-related clinical conditions. More generally, we demonstrate how multimodal neuroimaging investigations of training-induced neuroplasticity enable revealing novel anatomo-functional dissociations within frontal executive brain networks.CIB

Predictors for Returning to Paid Work after Transient Ischemic Attack and Minor Ischemic Stroke

This study aims to determine which factors within the first week after a first-ever transient ischemic attack (TIA) or minor ischemic stroke (MIS) are associated with stroke survivors’ ability to return to either partial or full time paid external work (RTpW). In this single-center prospective cohort study, we recruited 88 patients with first-ever TIA or MIS (NIHSS ≤ 5). Bivariate analyses were conducted between patients that did (RTpW) or did not return to paid work (noRTpW) within 7 days after stroke onset and at 3-months follow-up. Then, we conducted multivariate logistic and negative binomial regression analyses assessing (i) which factors are associated with RTpW at 3 months (ii) the likelihood that patients would RTpW at 3 months and (iii) the number of months necessary to RTpW. Overall, 43.2% of the patients did not RTpW at 3 months. At 3-months follow-up, higher anxiety/depression and fatigue-related disabilities were associated with noRTpW. Multivariate analysis showed that higher NIHSS scores at onset and hyperlipidemia (LDL cholesterol > 2.6 mmol/L or statins at stroke onset) were associated with noRTpW at 3 months. Stroke severity and/or newly diagnosed hypercholesterolemia at stroke onset in TIA or MIS patients were associated with not returning to paid work at 3 months