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Research at Mass General
Alexandra-Chloé Villani, PhDMember of the Faculty of MedicineMassachusetts General Hospital Cancer CenterHarvard Medical School
The Villani laboratory seeks to establish a comprehensive roadmap of the human immune system by achieving a higher resolution definition and functional characterization of cell subsets and rules governing immune response regulation, as a foundation to decipher how immunity is dysregulated in diseases. We use unbiased systems immunology approaches, cutting-edge immunogenomics, single-cell ‘multi-omics’ strategies, and integrative computational frameworks to empower the study and modeling of the immune system as a function of “healthy” and inflammatory states, disease progression, and response to treatment. Our multi-disciplinary team of immunologists, geneticist, computational biologists, and physicians work towards answering several key questions: Do we know all existing blood immune cell subsets? How do circulating immune cells mirror those in tissue microenvironment in the context of health and disease? Can we identify targets that would improve immunotherapy efficacy by increasing specificity? Collectively, our groundwork is paving the way for developing a human immune lexicon that is key to promoting effective bench-to-beside translation of findings.
Alexandra-Chloé Villani, PhDPrincipal Investigator
Our research program focuses on defining, at high-resolution, the pillars underlying healthy human immune responses as a foundation for understanding and modeling how immunity is dysregulated in diseases spectrums across chronic inflammation, autoimmunity and cancer (Villani et al. Ann Rev Immunol 2018).
Leveraging single-cell ‘omics’ to unravel new insights into human immune system
Achieving detailed understanding of the composition and function of the immune system at the fundamental unit of life — the cell — is essential to determining the prerequisites of health and disease. Historically, leukocyte populations have been defined by a combination of morphology, localization, functions, developmental origins, and the expression of a restricted set of markers. These strategies are inherently biased and recognized today as inadequate. Single-cell RNA sequencing (scRNAseq) analysis provides an unbiased, data-driven way of systematically detecting cellular states that can reveal diverse simultaneous facets of cellular identity, from discrete cell types to continuous dynamic transitions, which cannot be defined by a handful of pre-defined markers or for which markers are not yet known. We combine scRNAseq strategies together with in-depth follow-up profiling, phenotypic and functional characterization of prospectively isolated immune subsets defined by scRNAseq data to overcome such limitations. Our recent analyses of the human blood mononuclear phagocyte system resulted in the identification of six dendritic cell (DC), four monocyte, and one DC progenitor populations, thus revising the taxonomy of these cells (Villani et al., Science 2017). Noteworthy, five of these subsets had never been reported, illustrating the power of our integrative strategies to reopen the definition of these cell types, allowing for a more sophisticated and complete cell population overview. Our study highlighted the value of embarking on a comprehensive Human Cell Atlas initiative and offered a useful framework for conducting this kind of analysis on other cell types and tissues.
The Villani laboratory has developed in-depth expertise in single-cell ‘omics’ approaches, which are undoubtedly revolutionizing our understanding of biology. We adapted single-cell strategies to map X-chromosome inactivation across single-cells (Tukiainen, Villani et al., Nature 2017), and contributed in developing a new enrichment method enabling targeting the transcriptome of individual cells in pooled sequencing library (Ranu, Villani et al., Biorxiv 2017). We developed and implemented methods to study single-T cells (Villani et al., Methods MolBiol 2016), which have been used to study T cells infiltrates in melanoma lesions (Izar, et al., Science 2016).
We are currently contributing to the immune cell atlas effort by charting at high-resolution the human blood cellular landscape, with the goal of mapping all cell types with a frequency of at least ~0.1%. Our effort will result in developing better tools for the Immunology Community, including identifying minimal sets of most informative discriminatory markers per population and establishing “healthy” foundational knowledge reference dataset to study disease. Additionally, we are studying paired human tissues with blood to better establish how circulating immune cells mirror those in tissue microenvironment in the context of health and disease.
Deciphering immune-related adverse events (irAEs) induced by immune-checkpoint inhibitor (ICI) therapy.
While ICI therapy is revolutionizing the treatment of solid cancers, its success is currently being limited by treatment-induced irAEs resembling autoimmune diseases that are affecting nearly every organ system. With ICI becoming first- and second-line of cancer treatments, it is expected that the number of irAEs will continue rising and limit immunotherapy efficacy unless we find solutions. Our multi-disciplinary translational group of scientists and clinicians are thus working towards developing a better understanding of the biological players and underlying molecular and cellular mechanisms involved in driving irAEs by directly studying patient blood and matched affected tissue samples using a range of systems immunology, immunogenomics and single-cell ‘omics’ strategies. Our translational research program may result in identifying putative cellular components and mechanisms that could be (i) targeted in a ‘primary-prevention’ approach to preventirAE development (e.g.biomarkers), or (ii) targeted after onset of irAEs, without reducing the efficacy of the immunotherapy.
Establishing a human blood dendritic cell and monocyte atlas.
We isolated ~2400 cells enriched from the healthy human blood lineage− HLA-DR+ compartment and subjected them to single-cell RNA sequencing. This strategy, together with follow-up profiling and functional and phenotypic characterization, led us to update the original cell classification to include six DCs, four monocyte subtypes, and one conventional DC progenitor.
Villani AC, Sarkizova S, Hacohen N. Systems Immunology: learning the rules of the immune system. Annu Rev Immunol 2018; 36: 813-842.
Villani AC*†, Satija R*, ReynoldsG, Sarkizova S, Shekhar K, Fletcher J, Griesbeck M, Butler A, ZhengS, Lazo S, Jardine L, Dixon D, Stephenson E, Nilsson E, Grundberg I, McDonald D, Filby A, Li W, De Jager PL, Rozenblatt-Rosen O, Lane AA, Haniffa M, Regev A†, Hacohen N†. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes and progenitors. Science 2017; 356: 6335. pii: eaah4573.
Tukiainen T, Villani AC, Yen A, Rivas MA, Marshall JL, Satija R, Aguirre M,Gauthier L, Fleharty M, Kirby A, Cummings BB, Castel SE, Karczewski KJ, Aguet F, Byrnes A, GTEx Consortium, Lappalainen T, Regev A, Ardlie KG, Hacohen N, MacArthur DG. Landscape of X chromosome inactivation across human tissues. Nature 2017; 550(7675): 244-248.
Ranu N, Villani AC, Hacohen N, Blainey PC. Targeting individual cells by barcode in pooled sequence library. Biorxiv 2017;doi: https://doi.org/10.1101/178681.
Villani AC†, KarthikShekhar†. Single cell RNA sequencing of human T cells. Methods in Molecular Biology 2017; 1514: 203-239.
Olah M*, Patrick E*, Villani AC*, Xu J, White CC, Ryan KJ, Piehowski P, Kapasi A, Nejad P, Cimpean M, Connor S, Yung CJ, Frangieh M, McHenry A, Elyaman W, Petyuk V, Schneider JA, Bennett DA, De Jager PL, Bradshaw EM. A transcriptomic atlas of aged human microglia informs neurodegenerative disease studies. Nat Communications 2018; 9(1): 539.
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