Advances in high-dimensional mass cytometry cell and tissue analyses for translational biomarker discovery

Abstract

The systematic profiling of cellular functions and phenotypes, especially for cancer and inflammation diseases, enables patient stratification strategies and personalized medicine approaches. These studies include quantification of cell surface phenotypic and activation markers, and detection of secreted proteins and peptides. This information can aid discovery of both clinical biomarkers, as well as Ex Vivo/ In Vitro read-outs to guide development of novel therapeutics. The focus of this review is to highlight the value of the precision medicine data generated using novel high-dimensional technologies, such as mass cytometry (MC) and imaging MC, and to review emerging data tools which enable comprehensive data analysis and elucidation. Integration of these novel multiplex read-outs and corresponding mathematical analyses has facilitated discovery of previously unrecognized prognostic clinical biomarkers. During the last two decades our knowledge of cellular homeostasis during disease origination and progression has significantly advanced due to the systematic profiling of cellular functions and phenotypes, especially for immune-cell mediated pathologies [1,2]. In fact, many clinical trials now include cellular immunophenotyping as a biomarker component [3,4]. Patient specimens, often as small as a core needle biopsies or superfluous volumes of routinely collected fluids such as blood or sputum [5], are tested by a multitude of single cell profiling methods focusing on gaining a better understating of the cellular milieu. These studies include quantification of cell surface phenotypic and activation markers [6], ex-vivo response analysis to therapies [7], and detection of secreted proteins and peptides [8]. Multiplexed analyses throughout clinical trials have enabled the collection of valuable information from precious and limited patient specimens applied to investigate cellular disease perturbations. Ultimately these data aid in the development of disease diagnostic and prognostic tools, and more importantly determine patient stratification strategies which enable personalized medicine approaches. The focus of this review is to highlight the value of the translational data generated using novel technologies, such as mass cytometry (MC) and imaging MC, which has brought single cell immunophenotyping and imaging of the tumor microenvironment and other tissues to a new forefront, and to review emerging data tools which enable comprehensive data analysis and interpretation, often identifying previously unrecognized connections between cellular phenotypes and functions in healthy and diseased states [9][10][11][12].Although still in early development, MC based single cell immunophenotyping and analysis are steadily gaining recognition and becoming a mainstay in not only immune-mediated disease research, but in interrogating basic biology of other therapeutic targets [13][14][15][16]. MC or cytometry by time of flight (CyTOF) merges concepts of both flow cytometry and mass spectrometry [17,18]. This method r...