Mutations in STK11/LKB1 in non-small cell lung cancer (NSCLC) are associated with poor patient responses to immune checkpoint blockade (ICB), and introduction of a Stk11/Lkb1 (L) mutation into murine ...lung adenocarcinomas driven by mutant Kras and Trp53 loss (KP) resulted in an ICB refractory syngeneic KPL tumor. Mechanistically this occurred because KPL mutant NSCLCs lacked TCF1-expressing CD8 T cells, a phenotype recapitulated in human STK11/LKB1 mutant NSCLCs. Systemic inhibition of Axl results in increased type I interferon secretion from dendritic cells that expanded tumor-associated TCF1+PD-1+CD8 T cells, restoring therapeutic response to PD-1 ICB in KPL tumors. This was observed in syngeneic immunocompetent mouse models and in humanized mice bearing STK11/LKB1 mutant NSCLC human tumor xenografts. NSCLC-affected individuals with identified STK11/LKB1 mutations receiving bemcentinib and pembrolizumab demonstrated objective clinical response to combination therapy. We conclude that AXL is a critical targetable driver of immune suppression in STK11/LKB1 mutant NSCLC.
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•Lack of TCF1+ CD8 T cells underlies poor response of STK11 mutant NSCSLC to anti-PD-1•Axl inhibition induces type I interferon and expansion of TCF1+ CD8 T cells•Axl inhibition sensitizes STK11/LKB1 mutant NSCLC to anti-PD-1 therapy•Preliminary clinical data supports inhibition of Axl and PD-1 in STK11 mutant NSCLC
Li et al. provide mechanistic insight into why lung cancers with a common mutation (LKB1/STK11) are largely insensitive to immune therapy. The authors also demonstrate that inhibition of AXL activity in dendritic cells can restore sensitivity to immune therapy in LKB1/STK11 mutant lung cancer.
Multiple system atrophy (MSA) is a neurodegenerative disease that presents as an autonomic dysfunction in combination with varying degrees of parkinsonism and cerebellar ataxia. It comprises a ...pathologically widespread neuronal loss accompanied by gliosis in the basal ganglia, cerebellum, pons, inferior olivary nuclei, and spinal cord. As a rapidly progressive disorder, MSA develops with autonomic dysfunction and mobility problems in several years. These autonomic and motor function impairments severely disrupt the patients’ daily lives. Currently, the therapeutic management of this disease is only symptomatic. An early and accurate diagnosis is helpful not only in the clinical field but also in the research for new therapies. The biomarkers in cerebrospinal fluid (CSF) and serum facilitate the differential diagnosis of MSA when the disease is difficult to recognize based on the clinical features or even presymptomatic. This review will summarize the biomarkers present in CSF that are potential candidates to accurately differentiate MSA from other similar neurodegenerative disorders.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a first-line therapy for rapidly killing tumors such as those associated with non-small cell lung cancer by blocking ...oncogenic receptor signaling, but tumor relapse often occurs. Here, we have observed that hypofractionated EGFR TKI treatment (HypoTKI) is more potent than standard hyperfractionated EGFR TKI treatment (HyperTKI), and its antitumor effect associated with preventing tumor relapse depends on T cells. HypoTKI triggers greater innate sensing for type I IFN and CXCL10 production through the Myd88 signaling pathway to enhance tumor-specific T cell infiltration and reactivation. We also demonstrate that timely programmed cell death ligand-1 (PD-L1) blockade can synergize with HypoTKI to control advanced large tumors and effectively limit tumor relapse without severe side effects. Our study provides evidence for exploring the potential of a proper combination of EGFR TKIs and immunotherapy as a first-line treatment for treating EGFR-driven tumors.
DNA methylation is an epigenetic mechanism with the potential to regulate gene expression and affect plant phenotypes. Both hybridization and genome doubling may affect the DNA methylation status of ...newly formed allopolyploid plants. Previous studies demonstrated that changes in cytosine methylation levels and patterns were different among individual hybrid plant, therefore, studies investigating the characteristics of variation in cytosine methylation status must be conducted at the population level to avoid sampling error. In the present study, an F1 hybrid diploid population and three allotriploid populations with different heterozygosity originating from first-division restitution (FDR), second-division restitution (SDR), and post-meiotic restitution (PMR) 2n eggs of the same female parent were used to investigate cytosine methylation inheritance and variation relative to their common parents using methylation-sensitive amplification polymorphism (MSAP). The variation in cytosine methylation in individuals in each population exhibited substantial differences, confirming the necessity of population epigenetics. The total methylation levels of the diploid population were significantly higher than in the parents, but those of the three allotriploid populations were significantly lower than in the parents, indicating that both hybridization and polyploidization contributed to cytosine methylation variation. The vast majority of methylated status could be inherited from the parents, and the average percentages of non-additive variation were 6.29, 3.27, 5.49 and 5.07% in the diploid, FDR, SDR and PMR progeny populations, respectively. This study lays a foundation for further research on population epigenetics in allopolyploids.
Herein, we report that genetically programmable fusion cellular vesicles (Fus‐CVs) displaying high‐affinity SIRPα variants and PD‐1 can activate potent antitumor immunity through both innate and ...adaptive immune effectors. Dual‐blockade of CD47 and PD‐L1 with Fus‐CVs significantly increases the phagocytosis of cancer cells by macrophages, promotes antigen presentation, and activates antitumor T‐cell immunity. Moreover, the bispecific targeting design of Fus‐CVs ensures better targeting on tumor cells, but less on other cells, which reduces systemic side effects and enhances therapeutic efficacies. In malignant melanoma and mammary carcinoma models, we demonstrate that Fus‐CVs significantly improve overall survival of model animals by inhibiting post‐surgery tumor recurrence and metastasis. The Fus‐CVs are suitable for protein display by genetic engineering. These advantages, integrated with other unique properties inherited from source cells, make Fus‐CVs an attractive platform for multi‐targeting immune checkpoint blockade therapy.
Genetically programmable fusion cellular vesicles (Fus‐CVs) were developed to elicit potent antitumor immunity by concurrently blocking innate immune checkpoint CD47 and adaptive immune checkpoint PD‐L1. The Fus‐CVs represent a simple, safe and robust alternative to fusion proteins for multi‐targeting immune blockade checkpoint (ICB) therapy.
The lack of sufficient functional tumor-infiltrating lymphocytes in the tumor microenvironment (TME) is one of the primary indications for the poor prognosis of patients with cancer. In this study, ...we developed an Erbitux-based IL-21 tumor-targeting fusion protein (Erb-IL21) to prolong the half-life and improve the antitumor efficacy of IL-21. Compared with Erb-IL2, Erb-IL21 demonstrated much lower toxicity in vivo. Mechanistically, Erb-IL21 selectively expanded functional cytotoxic T lymphocytes but not dysfunctional CD8+ T cells in the TME. We observed that the IL-21-mediated antitumor effect largely depended on the existing intratumoral CD8+ T cells, instead of newly migrated CD8+ T cells. Furthermore, Erb-IL21 overcame checkpoint blockade resistance in mice with advanced tumors. Our study reveals that Erb-IL21 can target IL-21 to tumors and maximize the antitumor potential of checkpoint blockade by expending a subset of tumor antigen-specific CD8+ T cells to achieve effective tumor control.
Network security situation perception is to predict the probability of attacks, may occur in the future, by a variety of predicting methods, by recent network attacking data obtained from IDS ...(Intrusion Detection System). Neural Network model has many features, high degree of fault tolerance, associability, self-organizing and self-learning ability, and strong nonlinear mapping and generalization for a complex system, for example. Therefore, Neural Network was applied to the field of network security situation prediction. Adaptive Learning of neuron was introduced. It will be more flexibility to meet changing security environment of such a complex system requirements. The design and achievement of the adaptive learning neuron was stated in detail.
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