Group 1 innate lymphoid cells protect liver transplants from ischemia-reperfusion injury via an interferon-γ-mediated pathway.

As important immune regulatory cells, whether innate lymphoid cells (ILCs) are involved in liver transplantation (LT) remains unclear. In a murine orthotopic LT model, we dissected roles of ILCs in liver ischemia-reperfusion injury (IRI). Wild type (WT) grafts suffered significantly higher IRI in Rag2-γc double knockout (DKO) than Rag2 KO recipients, in association with downregulation of group 1 ILCs genes, including IFN-γ.

A multivalent binding model infers antibody Fc species from systems serology.

Systems serology aims to broadly profile the antigen binding, Fc biophysical features, immune receptor engagement, and effector functions of antibodies. This experimental approach excels at identifying antibody functional features that are relevant to a particular disease. However, a crucial limitation of this approach is its incomplete description of what structural features of the antibodies are responsible for the observed immune receptor engagement and effector functions.

Systems profiling reveals recurrently dysregulated cytokine signaling responses in ER+ breast cancer patients' blood.

Cytokines operate in concert to maintain immune homeostasis and coordinate immune responses. In cases of ER breast cancer, peripheral immune cells exhibit altered responses to several cytokines, and these alterations are correlated strongly with patient outcomes. To develop a systems-level understanding of this dysregulation, we measured a panel of cytokine responses and receptor abundances in the peripheral blood of healthy controls and ER breast cancer patients across immune cell types.

The structure is the message: Preserving experimental context through tensor decomposition.

Recent biological studies have been revolutionized in scale and granularity by multiplex and high-throughput assays. Profiling cell responses across several experimental parameters, such as perturbations, time, and genetic contexts, leads to richer and more generalizable findings. However, these multidimensional datasets necessitate a reevaluation of the conventional methods for their representation and analysis.

Integrative, high-resolution analysis of single cells across experimental conditions with PARAFAC2.

Effective tools for exploration and analysis are needed to extract insights from large-scale single-cell measurement data. However, current techniques for handling single-cell studies performed across experimental conditions (e.g.

Censored Least Squares for Imputing Missing Values in PARAFAC Tensor Factorization.

Tensor factorization is a dimensionality reduction method applied to multidimensional arrays. These methods are useful for identifying patterns within a variety of biomedical datasets due to their ability to preserve the organizational structure of experiments and therefore aid in generating meaningful insights. However, missing data in the datasets being analyzed can impose challenges.

Tensor modeling of MRSA bacteremia cytokine and transcriptional patterns reveals coordinated, outcome-associated immunological programs.

Methicillin-resistant (MRSA) bacteremia is a common and life-threatening infection that imposes up to 30% mortality even when appropriate therapy is used. Despite in vitro efficacy determined by minimum inhibitory concentration breakpoints, antibiotics often fail to resolve these infections in vivo, resulting in persistent MRSA bacteremia. Recently, several genetic, epigenetic, and proteomic correlates of persistent outcomes have been identified.

Systems profiling reveals recurrently dysregulated cytokine signaling responses in ER+ breast cancer patients' blood.

Cytokines mediate cell-to-cell communication across the immune system and therefore are critical to immunosurveillance in cancer and other diseases. Several cytokines show dysregulated abundance or signaling responses in breast cancer, associated with the disease and differences in survival and progression. Cytokines operate in a coordinated manner to affect immune surveillance and regulate one another, necessitating a systems approach for a complete picture of this dysregulation.

Dissecting signaling regulators driving AXL-mediated bypass resistance and associated phenotypes by phosphosite perturbations.

Receptor tyrosine kinase (RTK)-targeted therapies are often effective but invariably limited by drug resistance. A major mechanism of acquired resistance involves "bypass" switching to alternative pathways driven by non-targeted RTKs that restore proliferation. One such RTK is AXL whose overexpression, frequently observed in bypass resistant tumors, drives both cell survival and associated malignant phenotypes such as epithelial-to-mesenchymal (EMT) transition and migration.

Multivalent, asymmetric IL-2-Fc fusions show enhanced selectivity for regulatory T cells.

The cytokine interleukin-2 (IL-2) has the potential to treat autoimmune disease but is limited by its modest specificity toward immunosuppressive regulatory T (T) cells. IL-2 receptors consist of combinations of α, β, and γ chains of variable affinity and cell specificity. Engineering IL-2 to treat autoimmunity has primarily focused on retaining binding to the relatively T-selective, high-affinity receptor while reducing binding to the less selective, low-affinity receptor.

Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates.

Immunoglobulin G (IgG) antibodies coordinate immune effector responses by interacting with effector cells via fragment crystallizable γ (Fcγ) receptors. The IgG Fc domain directs effector responses through subclass and glycosylation variation. Although each Fc variant has been extensively characterized in isolation, during immune responses, IgG is almost always produced in Fc mixtures.

Analysis and modeling of cancer drug responses using cell cycle phase-specific rate effects.

Identifying effective therapeutic treatment strategies is a major challenge to improving outcomes for patients with breast cancer. To gain a comprehensive understanding of how clinically relevant anti-cancer agents modulate cell cycle progression, here we use genetically engineered breast cancer cell lines to track drug-induced changes in cell number and cell cycle phase to reveal drug-specific cell cycle effects that vary across time. We use a linear chain trick (LCT) computational model, which faithfully captures drug-induced dynamic responses, correctly infers drug effects, and reproduces influences on specific cell cycle phases.

Design of cell-type-specific hyperstable IL-4 mimetics via modular de novo scaffolds.

The interleukin-4 (IL-4) cytokine plays a critical role in modulating immune homeostasis. Although there is great interest in harnessing this cytokine as a therapeutic in natural or engineered formats, the clinical potential of native IL-4 is limited by its instability and pleiotropic actions. Here, we design IL-4 cytokine mimetics (denoted Neo-4) based on a de novo engineered IL-2 mimetic scaffold and demonstrate that these cytokines can recapitulate physiological functions of IL-4 in cellular and animal models.

Tensor-based insights into systems immunity and infectious disease.

Profiling immune responses across several dimensions, including time, patients, molecular features, and tissue sites, can deepen our understanding of immunity as an integrated system. These studies require new analytical approaches to realize their full potential. We highlight recent applications of tensor methods and discuss several future opportunities.

A stimulus-contingent positive feedback loop enables IFN-β dose-dependent activation of pro-inflammatory genes.

Type I interferons (IFN) induce powerful antiviral and innate immune responses via the transcription factor, IFN-stimulated gene factor (ISGF3). However, in some pathological contexts, type I IFNs are responsible for exacerbating inflammation. Here, we show that a high dose of IFN-β also activates an inflammatory gene expression program in contrast to IFN-λ3, a type III IFN, which elicits only the common antiviral gene program.

Mixed IgG Fc immune complexes exhibit blended binding profiles and refine FcR affinity estimates.

Unlabelled: Immunoglobulin (Ig)G antibodies coordinate immune effector responses by selectively binding to target antigens and then interacting with various effector cells via the Fcγ receptors. The Fc domain of IgG can promote or inhibit distinct effector responses across several different immune cell types through variation based on subclass and Fc domain glycosylation. Extensive characterization of these interactions has revealed how the inclusion of certain Fc subclasses or glycans results in distinct immune responses.

Addressing the genetic/nongenetic duality in cancer with systems biology.

The dogma that cancer is a genetic disease is being questioned. Recent findings suggest that genetic/nongenetic duality is necessary for cancer progression. A think tank organized by the Shraman Foundation's Institute for Theoretical Biology compiled key challenges and opportunities that theoreticians, experimentalists, and clinicians can explore from a systems biology perspective to provide a better understanding of the disease as well as help discover new treatment options and therapeutic strategies.

Live Cell Lineage Tracing of Dormant Cancer Cells.

Breast cancer is a leading cause of global cancer-related deaths, and metastasis is the overwhelming culprit of poor patient prognosis. The most nefarious aspect of metastasis is dormancy, a prolonged period between primary tumor resection and relapse. Current therapies are insufficient at killing dormant cells; thus, they can remain quiescent in the body for decades until eventually undergoing a phenotypic switch, resulting in metastases that are more adaptable and drug resistant.

A lineage tree-based hidden Markov model quantifies cellular heterogeneity and plasticity.

Individual cells can assume a variety of molecular and phenotypic states and recent studies indicate that cells can rapidly adapt in response to therapeutic stress. Such phenotypic plasticity may confer resistance, but also presents opportunities to identify molecular programs that could be targeted for therapeutic benefit. Approaches to quantify tumor-drug responses typically focus on snapshot, population-level measurements.

Systems approaches to uncovering the contribution of environment-mediated drug resistance.

Cancer drug response is heavily influenced by the extracellular matrix (ECM) environment. Despite a clear appreciation that the ECM influences cancer drug response and progression, a unified view of how, where, and when environment-mediated drug resistance contributes to cancer progression has not coalesced. Here, we survey some specific ways in which the ECM contributes to cancer resistance with a focus on how materials development can coincide with systems biology approaches to better understand and perturb this contribution.

Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection.

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells.

Dual data and motif clustering improves the modeling and interpretation of phosphoproteomic data.

Cell signaling is orchestrated in part through a network of protein kinases and phosphatases. Dysregulation of kinase signaling is widespread in diseases such as cancer and is readily targetable through inhibitors. Mass spectrometry-based analysis can provide a global view of kinase regulation, but mining these data is complicated by its stochastic coverage of the proteome, measurement of substrates rather than kinases, and the scale of the data.

Integrated Proteomics-Based Physical and Functional Mapping of AXL Kinase Signaling Pathways and Inhibitors Define Its Role in Cell Migration.

Unlabelled: To better understand the signaling complexity of AXL, a member of the tumor-associated macrophage (TAM) receptor tyrosine kinase family, we created a physical and functional map of AXL signaling interactions, phosphorylation events, and target-engagement of three AXL tyrosine kinase inhibitors (TKI). We assessed AXL protein complexes using proximity-dependent biotinylation (BioID), effects of AXL TKI on global phosphoproteins using mass spectrometry, and target engagement of AXL TKI using activity-based protein profiling. BioID identifies AXL-interacting proteins that are mostly involved in cell adhesion/migration.

A quantitative view of strategies to engineer cell-selective ligand binding.

A critical property of many therapies is their selective binding to target populations. Exceptional specificity can arise from high-affinity binding to surface targets expressed exclusively on target cell types. In many cases, however, therapeutic targets are only expressed at subtly different levels relative to off-target cells.