Alan G. Ramsay

Bio: Alan G. Ramsay is an academic researcher from King's College London. The author has contributed to research in topics: Chronic lymphocytic leukemia & T cell. The author has an hindex of 32, co-authored 89 publications receiving 4425 citations. Previous affiliations of Alan G. Ramsay include Rowett Research Institute & Queen Mary University of London.

Chronic lymphocytic leukemia T cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug

Abstract: Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4+ and CD8+ T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. This required direct contact and was inhibited by blocking adhesion molecules on CLL B cells. In T cells from patients with CLL and in T cells from healthy individuals that had been in contact with CLL cells, recruitment of key regulatory proteins to the immune synapse was inhibited. Treatment of autologous T cells and CLL cells with the immunomodulating drug lenalidomide resulted in improved synapse formation. These results define what we believe to be a novel immune dysfunction in T cells from patients with CLL that has implications for both autologous and allogeneic immunotherapy approaches and identifies repair of immune synapse defects as an essential step in improving cancer immunotherapy approaches.

Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm

Abstract: Plasticity is a hallmark of cells of the myelomonocytic lineage. In response to innate recognition or signals from lymphocyte subsets, mononuclear phagocytes undergo adaptive responses. Shaping of monocyte-macrophage function is an essential component of resistance to pathogens, tissue damage and repair. The orchestration of myelomonocytic cell function is a key element that links inflammation and cancer and provides a paradigm for macrophage plasticity and function. A better understanding of the molecular basis of myelomonocytic cell plasticity will open new vistas in immunopathology and therapeutic intervention.

T Cells with Chimeric Antigen Receptors Have Potent Antitumor Effects and Can Establish Memory in Patients with Advanced Leukemia

Abstract: Tumor immunotherapy with T lymphocytes, which can recognize and destroy malignant cells, has been limited by the ability to isolate and expand T cells restricted to tumor-associated antigens. Chimeric antigen receptors (CARs) composed of antibody binding domains connected to domains that activate T cells could overcome tolerance by allowing T cells to respond to cell surface antigens; however, to date, lymphocytes engineered to express CARs have demonstrated minimal in vivo expansion and antitumor effects in clinical trials. We report that CAR T cells that target CD19 and contain a costimulatory domain from CD137 and the T cell receptor ζ chain have potent non–cross-resistant clinical activity after infusion in three of three patients treated with advanced chronic lymphocytic leukemia (CLL). The engineered T cells expanded >1000-fold in vivo, trafficked to bone marrow, and continued to express functional CARs at high levels for at least 6 months. Evidence for on-target toxicity included B cell aplasia as well as decreased numbers of plasma cells and hypogammaglobulinemia. On average, each infused CAR-expressing T cell was calculated to eradicate at least 1000 CLL cells. Furthermore, a CD19-specific immune response was demonstrated in the blood and bone marrow, accompanied by complete remission, in two of three patients. Moreover, a portion of these cells persisted as memory CAR+ T cells and retained anti-CD19 effector functionality, indicating the potential of this major histocompatibility complex–independent approach for the effective treatment of B cell malignancies.

Succession of microbial consortia in the developing infant gut microbiome

Abstract: The colonization process of the infant gut microbiome has been called chaotic, but this view could reflect insufficient documentation of the factors affecting the microbiome. We performed a 2.5-y case study of the assembly of the human infant gut microbiome, to relate life events to microbiome composition and function. Sixty fecal samples were collected from a healthy infant along with a diary of diet and health status. Analysis of >300,000 16S rRNA genes indicated that the phylogenetic diversity of the microbiome increased gradually over time and that changes in community composition conformed to a smooth temporal gradient. In contrast, major taxonomic groups showed abrupt shifts in abundance corresponding to changes in diet or health. Community assembly was nonrandom: we observed discrete steps of bacterial succession punctuated by life events. Furthermore, analysis of ≈500,000 DNA metagenomic reads from 12 fecal samples revealed that the earliest microbiome was enriched in genes facilitating lactate utilization, and that functional genes involved in plant polysaccharide metabolism were present before the introduction of solid food, priming the infant gut for an adult diet. However, ingestion of table foods caused a sustained increase in the abundance of Bacteroidetes, elevated fecal short chain fatty acid levels, enrichment of genes associated with carbohydrate utilization, vitamin biosynthesis, and xenobiotic degradation, and a more stable community composition, all of which are characteristic of the adult microbiome. This study revealed that seemingly chaotic shifts in the microbiome are associated with life events; however, additional experiments ought to be conducted to assess how different infants respond to similar life events.

Macrophage plasticity and polarization in tissue repair and remodelling.

Abstract: Mononuclear phagocyte plasticity includes the expression of functions related to the resolution of inflammation, tissue repair and remodelling, particularly when these cells are set in an M2 or an M2-like activation mode. Macrophages are credited with an essential role in remodelling during ontogenesis. In extraembryonic life, under homeostatic conditions, the macrophage trophic and remodelling functions are recapitulated in tissues such as bone, mammary gland, decidua and placenta. In pathology, macrophages are key components of tissue repair and remodelling that occur during wound healing, allergy, parasite infection and cancer. Interaction with cells bearing stem or progenitor cell properties is likely an important component of the role of macrophages in repair and remodelling. These properties of cells of the monocyte-macrophage lineage may represent a tool and a target for therapeutic exploitation.

Determining cell type abundance and expression from bulk tissues with digital cytometry.

Abstract: Single-cell RNA-sequencing has emerged as a powerful technique for characterizing cellular heterogeneity, but it is currently impractical on large sample cohorts and cannot be applied to fixed specimens collected as part of routine clinical care. We previously developed an approach for digital cytometry, called CIBERSORT, that enables estimation of cell type abundances from bulk tissue transcriptomes. We now introduce CIBERSORTx, a machine learning method that extends this framework to infer cell-type-specific gene expression profiles without physical cell isolation. By minimizing platform-specific variation, CIBERSORTx also allows the use of single-cell RNA-sequencing data for large-scale tissue dissection. We evaluated the utility of CIBERSORTx in multiple tumor types, including melanoma, where single-cell reference profiles were used to dissect bulk clinical specimens, revealing cell-type-specific phenotypic states linked to distinct driver mutations and response to immune checkpoint blockade. We anticipate that digital cytometry will augment single-cell profiling efforts, enabling cost-effective, high-throughput tissue characterization without the need for antibodies, disaggregation or viable cells. CIBERSORTx, a suite of computational tools, enables inference of cell type abundance and cell-type-specific gene expression profiles from bulk RNA profiles.