Predicting and controlling the reactivity of immune cell populations against cancer

Heterogeneous cell populations form an interconnected network that determine their collective output. One example of such a heterogeneous immune population is tumor-infiltrating lymphocytes (TILs), whose output can be measured in terms of its reactivity against tumors. While the degree of reactivity varies considerably between different TILs, ranging from null to a potent response, the underlying network that governs the reactivity is poorly understood. Here, we asked whether one can predict and even control this reactivity. To address this we measured the subpopulation compositions of 91 TILs surgically removed from 27 metastatic melanoma patients. Despite the large number of subpopulations compositions, we were able to computationally extract a simple set of subpopulation-based rules that accurately predict the degree of reactivity. This raised the conjecture of whether one could control reactivity of TILs by manipulating their subpopulation composition. Remarkably, by rationally enriching and depleting selected subsets of subpopulations, we were able to restore anti-tumor reactivity to nonreactive TILs. Altogether, this work describes a general framework for predicting and controlling the output of a cell mixture

Observational multi-centre, prospective study to characterize novel pathogen-and host-related factors in hospitalized patients with lower respiratory tract infections and/or sepsis - the "TAILORED-Treatment" study

Background: The emergence and spread of antibiotic resistant micro-organisms is a global concern, which is largely attributable to inaccurate prescribing of antibiotics to patients presenting with non-bacterial infections. The use of 'omics' technologies for discovery of novel infection related biomarkers combined with novel treatment algorithms offers possibilities for rapidly distinguishing between bacterial and viral infections. This distinction can be particularly important for patients suffering from lower respiratory tract infections (LRTI) and/or sepsis as they represent a significant burden to healthcare systems. Here we present the study details of the TAILORED-Treatment study, an observational, prospective, multi-centre study aiming to generate a multi-parametric model, combining host and pathogen data, for distinguishing between bacterial and viral aetiologies in children and adults with LRTI and/or sepsis. Methods: A total number of 1200 paediatric and adult patients aged 1month and older with LRTI and/or sepsis or a non-infectious disease are recruited from Emergency Departments and hospital wards of seven Dutch and Israeli medical centres. A panel of three experienced physicians adjudicate a reference standard diagnosis for all patients (i.e., bacterial or viral infection) using all available clinical and laboratory information, including a 28-day follow-up assessment. Nasal swabs and blood samples are collected for multi-omics investigations including host RNA and protein biomarkers, nasal microbiota profiling, host genomic profiling and bacterial proteomics. Simplified data is entered into a custom-built database in order to develop a multi-parametric model and diagnostic tools fo

Tumor-specific Ab-mediated targeting of MHC-peptide complexes induces regression of human tumor xenografts in vivo

A cancer immunotherapy strategy is described herein that combines the advantage of the well established tumor targeting capabilities of high-affinity recombinant fragments of Abs with the known efficient, specific, and potent killing ability of CD8 T lymphocytes directed against highly antigenic MHC-peptide complexes. Structurally, it consists of a previously uncharacterized class of recombinant chimerical molecules created by the genetic fusion of single-chain (sc) Fv Ab fragments, specific for tumor cell surface antigens, to monomeric scHLA-A2 complexes containing immunodominant tumor- or viral-specific peptides. The fusion protein can induce very efficiently tumor cell lysis, regardless of the expression of self peptide-MHC complexes. Moreover, these molecules exhibited very potent antitumor activity in vivo in nude mice bearing preestablished human tumor xenografts. These in vitro and in vivo results suggest that recombinant scFv-MHC-peptide fusion molecules could represent an approach to immunotherapy, bridging Ab and T lymphocyte attack on cancer cells

Development and testing of TraumaGameplay: An iterative experimental approach using the trauma film paradigm.

Background: Vivid trauma-related intrusions are a hallmark symptom of posttraumatic stress disorder (PTSD), and may be involved in its onset. Effective interventions to reduce intrusions and to potentially prevent the onset of subsequent PTSD are scarce. Studies suggest that playing the videogame Tetris, shortly after watching aversive film clips, reduces subsequent intrusions. Other studies have shown that taxing working memory (WM) while retrieving an emotional memory reduces the memory’s vividness and emotionality. Objective: We developed TraumaGameplay (TGP), a gaming app designed to reduce intrusions. This paper describes two successive experiments to determine whether playing TGP without memory retrieval (regular TGP) or TGP with memory retrieval (dual-task TGP) reduces intrusion frequency at one week compared to a no-game control. Method: For both experiments, healthy university students were recruited. Experiment 1: 92 participants were exposed to a trauma film and randomized to (1) regular TGP1 (n = 31), (2) dual-task TGP1 (n = 31) or (3) control (n = 30). In experiment 2, 120 healthy students were exposed to a trauma film and randomized to (1) regular TGP2 (n = 30), (2) dual-task TGP2 (n = 29), (3) recall only (n = 31) or (4) control (n = 30). Results: We found no significant difference between conditions on the number of intrusions for either playing regular TGP or dual-task TGP in both experiment 1 and experiment 2. Conclusion: Our results could not replicate earlier promising findings from preceding experimental research. Several reasons may underpin this difference ranging from the visuospatial videogame used in our experiments to the method of the experiment to the difficulties of replicability in general

A multifaceted 'omics' approach for addressing the challenge of antimicrobial resistance

The inappropriate use of antibiotics has severe global health and economic consequences, including the emergence of antibiotic-resistant bacteria. A major driver of antibiotic misuse is the inability to accurately distinguish between bacterial and viral infections based on currently available diagnostic solutions. A multifaceted 'omics' approach that integrates personalized patient data such as genetic predisposition to infections (genomics), natural microbiota composition and immune response to infection (proteomics and transcriptomics) together with comprehensive pathogen profiling has the potential to help physicians improve their antimicrobial prescribing practices. In this respect, the EU has funded a multidisciplinary project (TAILORED-Treatment) that will develop novel omics-based personalized treatment schemes that have the potential to reduce antibiotic consumption, and help limiting the spread of antibiotic resistance