The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.

Angiogenesis and increased permeability of the blood-brain barrier have been reported to occur in animal models of Parkinson's disease and l-dopa-induced dyskinesia, but the significance of these phenomena has remained unclear. Using a validated rat model of l-dopa-induced dyskinesia, this study demonstrates that chronic treatment with l-dopa dose dependently induces the expression of vascular endothelial growth factor in the basal ganglia nuclei. Vascular endothelial growth factor was abundantly expressed in astrocytes and astrocytic processes in the proximity of blood vessels. When co-administered with l-dopa, a small molecule inhibitor of vascular endothelial growth factor signalling significantly attenuated the development of dyskinesia and completely blocked the angiogenic response and associated increase in blood-brain barrier permeability induced by the treatment. The occurrence of angiogenesis and vascular endothelial growth factor upregulation was verified in post-mortem basal ganglia tissue from patients with Parkinson's disease with a history of dyskinesia, who exhibited increased microvascular density, microvascular nestin expression and an upregulation of vascular endothelial growth factor messenger ribonucleic acid. These congruent findings in the rat model and human patients indicate that vascular endothelial growth factor is implicated in the pathophysiology of l-dopa-induced dyskinesia and emphasize an involvement of the microvascular compartment in the adverse effects of l-dopa pharmacotherapy in Parkinson's disease.

Background Neural habituation, the decrease in brain response to repeated stimulation, is a basic form of learning. There is strong evidence for behavioral and physiological habituation deficits in schizophrenia, and one previous study found reduced neural habituation within the hippocampus. However, it is unknown whether neural habituation deficits are specific to faces and limited to the hippocampus. Here we studied habituation of several brain regions in schizophrenia, using both face and object stimuli. Post-scan memory measures were administered to test for a link between hippocampal habituation and memory performance. Methods During an fMRI scan, 23 patients with schizophrenia and 21 control subjects viewed blocks of a repeated neutral face or neutral object, and blocks of different neutral faces and neutral objects. Habituation in the hippocampus, primary visual cortex and fusiform face area (FFA) was compared between groups. Memory for faces, words, and word pairs was assessed after the scan. Results Patients showed reduced habituation to faces in the hippocampus and primary visual cortex, but not the FFA. Healthy control subjects exhibited a pattern of hippocampal discrimination that distinguished between repeated and different images for both faces and objects, and schizophrenia patients did not. Hippocampal discrimination was positively correlated with memory for word pairs. Conclusion Patients with schizophrenia showed reduced habituation of the hippocampus and visual cortex, and a lack of neural discrimination between old and new images in the hippocampus. Hippocampal discrimination correlated with memory performance, suggesting reduced habituation may contribute to the memory deficits commonly observed in schizophrenia.

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IntroductionThe glioblastoma (GBM) immune microenvironment is highly suppressive as it targets and hinders multiple components of the immune system. Checkpoint blockade (CB) is being evaluated for GBM patients. However, biomarker analyses suggest that CB monotherapy may be effective only in a small fraction of GBM patients. We hypothesized that activation of antigen presentation would increase the therapeutic response to PD-1 blockade.ResultsWe show that activating DCs through TLR3 agonists enhances the anti-tumor immune response to CB and increases survival in GBM. Mice treated with TLR3 agonist poly(I:C) and anti-PD-1 demonstrated increased DC activation and increased T cell proliferation in tumor draining lymph nodes. We show that DCs are necessary for the improved anti-tumor immune response.ConclusionsThis study suggests that augmenting antigen presentation is an effective multimodal immunotherapy strategy that intensifies anti-tumor responses in GBM. Specifically, these data represent an expanded role for TLR3 agonists as adjuvants to CB.MethodsUsing a preclinical model of GBM, we tested the efficacy of combinatorial immunotherapy with anti-PD-1 and TLR3 agonist, poly(I:C). Characterization of the immune response in tumor infiltrating immune cells and in secondary lymphoid organs was performed. Additionally, dendritic cell (DC) depletion experiments were performed.

Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

OBJECTIVEIntramedullary spinal cord tumors comprise 1%–10% of all childhood central nervous system neoplasms, with astrocytomas representing the most common subtype. Due to their rarity and poor prognosis, large population-based studies are needed to assess the epidemiology and survival risk factors associated with these tumors in the hope of improving outcome. The authors undertook this retrospective study to explore factors that may influence survival in pediatric patients with spinal cord astrocytomas.METHODSUtilizing the Surveillance, Epidemiology, and End Results (SEER) database, a prospective cancer registry, the authors retrospectively assessed survival in histologically confirmed, primary spinal cord astrocytomas in patients 21 years of age and younger. Survival was described with Kaplan-Meyer curves, and a multivariate regression analysis was used to assess the association of several variables with survival while controlling for confounding variables.RESULTSThis analysis of 348 cases showed that age (hazard ratio [HR] 1.05, 95% CI 1.01–1.09, p = 0.017), nonwhite race (HR 1.74, 95% CI 1.11–2.74, p = 0.014), high-grade tumor status (HR 14.67, 95% CI 6.69–32.14, p < 0.001), distant or invasive extension of the tumor (HR 2.37, 95% CI 1.02–5.49, p = 0.046), and radiation therapy (HR 3.74, 95% CI 2.18–6.41, p < 0.001) were associated with decreased survival. Partial resection (HR 0.37, 95% CI 0.16–0.83, p = 0.017) and gross-total resection (HR 0.39, 95% CI 0.16–0.95, p = 0.039) were associated with improved survival.CONCLUSIONSYounger age appears to be protective, while high-grade tumors have a much worse prognosis. Early diagnosis and access to surgery appears necessary for improving outcomes, while radiation therapy has an unclear role. There is still much to learn about this disease in the hope of curing children with the misfortune of having one of these rare tumors.

The observation of reduced temporal organisation in the patient group is consistent with the proposal that the memory deficit in schizophrenia can be characterised as a deficit in contextual processing.