Explore the vast range of titles available.

Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1 + T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent ‘back-signaling’ in CD4 + T cells, which prevented activation, reduced T H 1-polarization and directed T H 17-differentiation. PD-L1 signaling also induced an anergic T-bet − IFN-γ − phenotype in CD8 + T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1 + T cells restrained effector T cells via the canonical PD-L1–PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1 + T cells engaged PD-1 + macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1 + T cells have diverse tolerogenic effects on tumor immunity. PD-L1 on tumor cells exerts an important dampening effect on T cells via their expression of PD-1. Miller and colleagues find that PD-L1 ‘back-signaling’ into T cells and macrophages can also dampen immune responses within the tumor microenvironment.

The drivers and the specification of CD4 + T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T H -program. Specifically, CD11b + CD103 − DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 neg tumor-promoting IL-10 + IL-17 + IFNγ +  regulatory CD4 + T cells. The balance between this distinctive T H program and canonical FoxP3 +  T REGS is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T H -signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b + CD103 − DC promote CD4 + T cell tolerance in PDA which may underscore its resistance to immunotherapy. Pancreatic ductal adenocarcinoma is characterized by a highly immunosuppressive tumour microenvironment. Here, the authors show that specialized subsets of tumour-infiltrating dendritic cells induce distinct CD4 + T cell programs and specifically identify a CD103 – CD11b + subset which induces tumor-promoting FoxP3 – Type-1 regulatory T cells.

The drivers and the specification of CD4 T cell differentiation in the tumor microenvironment and their contributions to tumor immunity or tolerance are incompletely understood. Using models of pancreatic ductal adenocarcinoma (PDA), we show that a distinct subset of tumor-infiltrating dendritic cells (DC) promotes PDA growth by directing a unique T -program. Specifically, CD11b CD103 DC predominate in PDA, express high IL-23 and TGF-β, and induce FoxP3 tumor-promoting IL-10 IL-17 IFNγ regulatory CD4 T cells. The balance between this distinctive T program and canonical FoxP3 T is unaffected by pattern recognition receptor ligation and is modulated by DC expression of retinoic acid. This T -signature is mimicked in human PDA where it is associated with immune-tolerance and diminished patient survival. Our data suggest that CD11b CD103 DC promote CD4 T cell tolerance in PDA which may underscore its resistance to immunotherapy.

Response to cancer immunotherapy in primary versus metastatic disease has not been well-studied. We found primary pancreatic ductal adenocarcinoma (PDA) is responsive to diverse immunotherapies whereas liver metastases are resistant. We discovered divergent immune landscapes in each compartment. Compared to primary tumor, liver metastases in both mice and humans are infiltrated by highly anergic T cells and MHCII lo IL10 + macrophages that are unable to present tumor-antigen. Moreover, a distinctive population of CD24 + CD44 − CD40 − B cells dominate liver metastases. These B cells are recruited to the metastatic milieu by Muc1 hi IL18 hi tumor cells, which are enriched >10-fold in liver metastases. Recruited B cells drive macrophage-mediated adaptive immune-tolerance via CD200 and BTLA. Depleting B cells or targeting CD200/BTLA enhanced macrophage and T-cell immunogenicity and enabled immunotherapeutic efficacy of liver metastases. Our data detail the mechanistic underpinnings for compartment-specific immunotherapy-responsiveness and suggest that primary PDA models are poor surrogates for evaluating immunity in advanced disease.

Allosteric regulation enables fine-tuned control of enzyme activity in response to cellular signals, yet its molecular basis often remains unclear. Phosphofructokinase-1 (PFK), the rate-limiting enzyme of glycolysis, is a paradigmatic, well-conserved system whose reaction kinetics conform to the Monod-Wyman-Changeux model of allostery. However, X-ray crystal structures of bacterial PFK orthologs in distinct ligand-bound states do not show the consistent, concerted structural rearrangements expected for classical \"relaxed\" and \"tense\" states, revealing a decades-long disconnect between structure and function. We resolve this paradox by integrating biophysical and computational approaches to show that activator and inhibitor binding to the same allosteric pocket differentially reweight the conformational ensemble of PFK. Activator binding stabilizes conformational substates that preorganize the catalytic site, whereas inhibitor binding upweights apo-like, catalytically incompetent substates. These findings establish an ensemble-based mechanism for PFK regulation and provide an energetic framework for understanding the expanded allosteric architecture of higher PFK orthologs.

Quantitative tools to compile and analyze biomolecular interactions among chemically diverse binding partners would improve therapeutics design and aid in the study of molecular evolution. Here we present MAGPIE (Mapping Areas of Genetic Parsimony In Epitopes), a publicly available software package for simultaneously visualizing and analyzing thousands of interactions between a single protein or small molecule ligand (the \"target\") and all of its protein binding partners (\"binders\"). MAGPIE generates an interactive 3D visualization from a set of protein complex structures that share the target ligand, as well as sequence logo-style amino acid frequency graphs that show all the amino acids from the set of protein binders that interact with user-defined target ligand positions or chemical groups. MAGPIE highlights all the salt bridge and hydrogen bond interactions made by the target in the visualization and as separate amino acid frequency graphs. Finally, MAGPIE collates the most common target-binder interactions as a list of \"hotspots,\" which can be used to analyze trends or guide the de novo design of protein binders. As an example of the utility of the program, we used MAGPIE to probe how two ligands bind orthologs of a well-conserved glycolytic enzyme for a detailed understanding of evolutionarily conserved interactions involved in its activation and inhibition. MAGPIE is implemented in Python 3 and freely available at https://github.com/glasgowlab/MAGPIE, along with sample datasets, usage examples, and helper scripts to prepare input structures.Competing Interest StatementThe authors have declared no competing interest.Footnotes* We expanded MAGPIE to include several additional features and added helper scripts to prepare input structures. We fleshed out the manuscript to include these updates, as well as our application of MAGPIE to explore how bacterial orthologs of the glycolytic enzyme phosphofructokinase-1 can interact with allosteric ligands.* https://colab.research.google.com/github/glasgowlab/MAGPIE/blob/GoogleColab/MAGPIE_COLAB.ipynb