The role and uses of antibodies in COVID-19 infections: a living review

Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity

T cell phenotypes in COVID-19 - a living review

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients’ long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation

Multi-omics analysis and modelling of T cell immunity and interferon signalling pathways for engineered T cell therapy

This thesis examines the nature of T cells through the lens of genomics. It delves into type I interferon (IFN)-mediated signalling in the tumour microenvironment (TME), focusing on the GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway, and explores novel strategies to optimise T cell-based immunotherapy for triple-negative breast cancer (TNBC). In the first chapter, gene expression patterns of distinct T cell subtypes are studied to gain insight into the diverse T cell landscape. Cell type annotation methods are evaluated for their ability to identify closely-related T cell populations in single-cell RNA sequencing (scRNA-seq) data. In the following chapter, single-cell and spatial transcriptomics methods, mainly scRNA-seq, single-cell immune profiling, Slide-seq, in situ sequencing and Molecular Cartography enable the comprehensive analysis of immune infiltrates in tissue biopsies from patients with TNBC. The advantages and limitations of emerging spatial transcriptomics technologies are put into context. Tumour-infiltrating T cells were characterised at varying levels of resolution and cGAS was found to be most highly expressed in proliferating T cells. Tissue-wide spatial patterns revealed a strong relationship between programmed cell death-1/programmed cell death ligand-1 and cGAS but not STING. In addition, gene transcripts encoding the downstream protein kinase TANK-binding kinase 1 were found to spatially associate with hypoxia markers. Finally, T cells genetically engineered to express chimeric antigen receptors (CARs) are investigated using a systems biology approach. An agent-based model is developed to explore the effect of CAR tuning on on-target off-tumour toxicity and therapy efficacy. Gene regulatory networks are used to present readily testable hypotheses for combination strategies using immune checkpoint inhibitors, oncolytic viruses, and cGAS-STING-targeting treatments to potentiate anti-tumour responses. The work presented therein will feed into a novel computational framework to enable the modelling of patient-specific responses to T cell-based immunotherapy and synergistic combinations