IMMUNOLOGY AND INFLAMMATORY DISEASES
Villani Laboratory: Alexandra-Chloe Villani, PhD
Explore This Lab
The Villani Laboratory at Massachusetts General Hospital research program aims to establish a comprehensive roadmap of the human immune system through achieving a higher resolution definition and functional characterization of cell subsets and rules governing immune response regulation as a foundation for deciphering how immunity is dysregulated in diseases. We are using unbiased systems immunology approaches, cutting-edge immunogenomics, single-cell ‘multi-omics’ strategies and integrative computational frameworks empowering the study and modeling of the immune system as a function of healthy and inflammatory states, disease progression and response to treatment. Our multidisciplinary team of immunologists, geneticists, computational biologists and physicians are working 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?
- What are the biological players and mechanisms driving immune-related adverse events induced by immune-checkpoint inhibitor therapy?
- Can we identify targets that would improve immunotherapy efficacy by increasing specificity?
Collectively, our groundwork is paving the way for developing a comprehensive human immune lexicon that is key to promoting effective bench-to-beside translation of findings.
The Villani Laboratory at Massachusetts General Hospital 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. The lab emphasizes the development and application of unbiased systems immunology and genomics approaches that directly survey the human immune system in healthy and patient-derived samples, thus avoiding extrapolations from animal models that at times fail to validate in human clinical trials.
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 single cell ‘omics’ 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. 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 – from redefining our understanding of the types of cells, to translating this knowledge to better understand disease phenotypes and the implications of this to therapeutics. We are currently contributing to the immune cell atlas effort by helping chart at high resolution the human blood cellular landscape. 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. 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.
Developing and Implementing New Single-Cell Strategies to Empower Translational Efforts
We adapted single cell strategies to map X-chromosome inactivation across single-cells and contributed in developing a new enrichment method enabling targeting the transcriptome of individual cells in pooled sequencing library. Additionally, we developed and implemented single cell experimental and computational methods to study T cells, which have been used to study T cells infiltrates in melanoma lesions, and further adapted such framework to study human microglia.
Enhancing our Understanding of Mononuclear Phagocyte (MP) Contribution in Promoting Healthy and Disease States
DCs, monocytes and macrophages together comprise the MP system, which is specialized in initiating and regulating immune response. Functional heterogeneity within MP is thought to be a key mechanism by which the immune system interprets a stimulus and produces the appropriate response. Given the central role of these cells, substantial evidence unsurprisingly supports their contribution to immune dysfunction and human diseases including cancer. Building on our analyses of healthy human blood, we are currently expanding our research program to answer the following three key questions in order to further establish how to best leverage human MPs as more ideal targets for therapeutic immune modulation:
- What are the differences in MPs subsets, states and function between cells found in human blood versus in different lymphoid and non-lymphoid tissues in healthy steady-state?
- How do acute inflammatory responses affect these different MPs subsets in human blood and tissue in vivo, and which subsets are mobilized to travel from blood to tissue over time?
- What MPs subsets are defectively enriched or depleted in patients’ tumors and inflammatory lesions, and with which other cell types do these subsets communicate?
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. Since most cancer patients have no autoimmunity family history, this suggests that ICI treatments are triggering cascades of events tilting the natural mechanisms of the immune system away from tolerance. 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 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 nominating putative cellular components and mechanisms that could be (i) targeted in a ‘primary-prevention’ approach to prevent irAE development (e.g,. biomarkers), or (ii) targeted after onset of irAEs, without reducing the efficacy of the immunotherapy.
Alexandra-Chloe Villani, PhD
Director, Single-Cell Genomics Program, Center for Immunology and Inflammatory Diseases
Assistant Professor of Medicine, Harvard Medical School
Associate Scientist, Broad Institute of MIT and Harvard
- Mazen Nasrallah, MD
- Molly Fisher Thomas, MD, PhD
- Daniel Zlotoff, MD, PhD
- Kasidet Manakongtreecheep, BSc