Immunologic signatures of response and resistance to nivolumab with ipilimumab in advanced metastatic cancer.

Identifying pan-tumor biomarkers that predict responses to immune checkpoint inhibitors (ICI) is critically needed. In the AMADEUS clinical trial (NCT03651271), patients with various advanced solid tumors were assessed for changes in intratumoral CD8 percentages and their response to ICI. Patients were grouped based on tumoral CD8 levels: those with CD8 <15% (CD8-low) received nivolumab (anti-PD-1) plus ipilimumab (anti-CTLA4) and those with CD8 ≥15% (CD8-high) received nivolumab monotherapy.

Leveraging the histidine kinase-phosphatase duality to sculpt two-component signaling.

Bacteria must constantly probe their environment for rapid adaptation, a crucial need most frequently served by two-component systems (TCS). As one component, sensor histidine kinases (SHK) control the phosphorylation of the second component, the response regulator (RR). Downstream responses hinge on RR phosphorylation and can be highly stringent, acute, and sensitive because SHKs commonly exert both kinase and phosphatase activity.

Multimodal Control of Bacterial Gene Expression by Red and Blue Light.

By applying sensory photoreceptors, optogenetics realizes the light-dependent control of cellular events and state. Given reversibility, noninvasiveness, and exquisite spatiotemporal precision, optogenetic approaches enable innovative use cases in cell biology, synthetic biology, and biotechnology. In this chapter, we detail the implementation of the pREDusk, pREDawn, pCrepusculo, and pAurora optogenetic circuits for controlling bacterial gene expression by red and blue light, respectively.

Inosine Induces Stemness Features in CAR T cells and Enhances Potency.

Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8 CAR T cells mediate Ado-induced immunosuppression through CD39/73-dependent Ado production. Knockout of CD39, CD73 or A2aR had modest effects on exhausted CAR T cells, whereas overexpression of Ado deaminase (ADA), which metabolizes Ado to inosine (INO), induced stemness features and potently enhanced functionality. Similarly, and to a greater extent, exposure of CAR T cells to INO augmented CAR T cell function and induced hallmark features of T cell stemness.

Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state.

Cell cycle (CC) facilitates cell division via robust, cyclical gene expression. Protective immunity requires the expansion of pathogen-responsive cell types, but whether CC confers unique gene expression programs that direct the subsequent immunological response remains unclear. Here, we demonstrate that single macrophages (MFs) adopt different plasticity states in CC, which leads to heterogeneous cytokine-induced polarization, priming, and repolarization programs.

Divergent clonal differentiation trajectories of T cell exhaustion.

Chronic antigen exposure during viral infection or cancer promotes an exhausted T cell (Tex) state with reduced effector function. However, whether all antigen-specific T cell clones follow the same Tex differentiation trajectory remains unclear. Here, we generate a single-cell multiomic atlas of T cell exhaustion in murine chronic viral infection that redefines Tex phenotypic diversity, including two late-stage Tex subsets with either a terminal exhaustion (Tex) or a killer cell lectin-like receptor-expressing cytotoxic (Tex) phenotype.

Distribution of HPV Subtypes in Diverse Anogenital and Oral Samples from Women and Correlation of Infections with Neoplasia of the Cervix.

Background: Cancers and intraepithelial lesions of different anogenital areas as well as oral cancer are associated with human papilloma virus (HPV) infections.

Methods: In this study cervical, vaginal, vulvar, anal, and oral samples were taken from 509 patients visiting our dysplasia consultation clinic. HPV genotyping was performed using the EUROArray HPV test.

Bystander T cells in cancer immunology and therapy.

Cancer-specific T cells are required for effective anti-cancer immunity and have a central role in cancer immunotherapy. However, emerging evidence suggests that only a small fraction of tumor-infiltrating T cells are cancer specific, and T cells that recognize cancer-unrelated antigens (so-called 'bystanders') are abundant. Although the role of cancer-specific T cells in anti-cancer immunity has been well established, the implications of bystander T cells in tumors are only beginning to be understood.

Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation.

Pediatric gliomas comprise a broad range of brain tumors derived from glial cells. While high-grade gliomas are often resistant to therapy and associated with a poor outcome, children with low-grade gliomas face a better prognosis. However, the treatment of low-grade gliomas is often associated with severe long-term adverse effects.

Clonal diversity and genetic variation of the sedge in an alpine fen depend on soil nutrients.

In this study we analysed the impact of water regime and soil nutrients on the clonal diversity and genetic variation of the sedge in a central alpine fen. For our analysis, we established 16 study plots randomly distributed over the fen. We determined the exact elevation of each plot as an indicator for the water regime and measured the content of phosphorous and potassium in the soil of each plot.

Effects of Birch Polypore Mushroom, Piptoporus betulinus (Agaricomycetes), the "Iceman's Fungus", on Human Immune Cells.

Piptoporus betulinus, the mushroom that has been carried by Ötzi the "Iceman", has a long tradition of use in medicinal practice for its antiseptic, anticancer, and immune-enhancing properties. With this study, we aimed to investigate the immunomodulatory effects of P. betulinus on primary human immunocompetent cells.

CD40-signalling abrogates induction of RORγt Treg cells by intestinal CD103 DCs and causes fatal colitis.

Immune homeostasis in intestinal tissues depends on the generation of regulatory T (Treg) cells. CD103 dendritic cells (DCs) acquire microbiota-derived material from the gut lumen for transport to draining lymph nodes and generation of receptor-related orphan γt (RORγt) Helios-induced Treg (iTreg) cells. Here we show CD40-signalling as a microbe-independent signal that can induce migration of CD103 DCs from the lamina propria (LP) to the mesenteric lymph nodes.

Effects of Inonotus hispidus Extracts and Compounds on Human Immunocompetent Cells.

is used as a traditional medicine in China. Previous investigations revealed promising immunomodulatory activity of fruit body extracts of . Bioactivity-guided fractionation showed that hispolon and hispidin were active substances.

How type 1 fimbriae help Escherichia coli to evade extracellular antibiotics.

To survive antibiotics, bacteria use two different strategies: counteracting antibiotic effects by expression of resistance genes or evading their effects e.g. by persisting inside host cells.

Memory-based decision-making with heuristics: evidence for a controlled activation of memory representations.

Many of our daily decisions are memory based, that is, the attribute information about the decision alternatives has to be recalled. Behavioral studies suggest that for such decisions we often use simple strategies (heuristics) that rely on controlled and limited information search. It is assumed that these heuristics simplify decision-making by activating long-term memory representations of only those attributes that are necessary for the decision.

Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity.

Lack of immunological tolerance against self-antigens results in autoimmune disorders. During onset of autoimmunity, dendritic cells (DCs) are thought to be critical for priming of self-reactive T cells that have escaped tolerance induction. However, because DCs can also induce T cell tolerance, it remains unclear whether DCs are required under steady-state conditions to prevent autoimmunity.

Targeting HIV-1 Gag into the defective ribosomal product pathway enhances MHC class I antigen presentation and CD8+ T cell activation.

The main source for endogenous peptides presented by the MHC class I (MHC-I) pathway are de novo-synthesized proteins which are degraded via the ubiquitin proteasome pathway. Different MHC-I Ag pools can be distinguished: first, short-lived defective ribosomal products, which are degraded in concert with or shortly after their synthesis, and, second, functional proteins that enter the standard protein life cycle. To compare the contribution of these two Ag sources to the generation of MHC-I-presented peptides, we established murine cell lines which express as a model Ag the HIV-1 Gag polyprotein fused to ubiquitin (Ub) carrying the epitope SIINFEKL (SL).