= Emerging. More than 5 years before clinical availability. (16.60%, 2024)
= Expected to be clinically available in 1 to 4 years. (37.02%, 2024)
= Clinically available now. (46.38%, 2024)
MSACL 2024 : Angelo

MSACL 2024 Abstract

Self-Classified Topic Area(s): Imaging > Imaging > none

Podium Presentation in De Anza 1 on Thursday at 15:25 (Chair: Surendra Dasari / Angela Kruse)

Spatial Framework for Understanding Immune Tolerance in Human Health and Disease

Michael Angelo, MD, PhD (Presenter)
Stanford University School of Medicine

Presenter Bio: Michael Angelo, MD PhD is a board-certified pathologist in the department of Pathology at Stanford University School of Medicine. Dr. Angelo is a leader in high-dimensional imaging with expertise in tissue homeostasis, tumor immunology, and infectious disease. His lab has pioneered the construction and development of Multiplexed Ion Beam Imaging by time of flight (MIBI-TOF). MIBI-TOF uses secondary ion mass spectrometry and metal-tagged antibodies to achieve rapid, simultaneous imaging of dozens of proteins at subcellular resolution. His lab used this technology to discover previously unknown rule sets governing the spatial organization and cellular composition of immune and stromal cells within the tumor microenvironment in triple-negative breast cancer and ductal carcinoma in situ. This effort has led to ongoing work aimed to define broader structural mechanisms that promote tolerogenic niches in cancer, tuberculosis, and the maternal-fetal interface. His lab is expanding this spatial biology framework to leverage new technologies that can map the spatial distribution of transcripts, lipids, and glycans. Dr. Angelo is the recipient of 2014 NIH Director’s Early Independence, 2020 DOD Era of Hope Award and is a principal investigator on multiple extramural awards from the National Cancer Institute, Breast Cancer Research Foundation, Parker Institute for Cancer Immunotherapy, the Bill and Melinda Gates Foundation, and steering committee co-director of the Human Biomolecular Atlas (HuBMAP) initiative.


The focus of our work is to understand how normative pathways for immune tolerance are hijacked in disease. Progression to metastatic cancer, delivery of a healthy full-term infant, and pulmonary tuberculosis (TB) each occur when the immune system acquires tolerance to foreign antigens. These programs are mediated through an evolving spatiotemporal network involving dozens of cell types and multiple organ sites. Consequently, understanding them requires technical approaches to identify these cell types and their functions within intact human tissue. To unravel this connection between tissue structure and function, we have developed a spatial biology framework for studying these processes. In 2017, we created a new type of ion microscope for high-dimensional subcellular imaging of intact archival human tissue from medical center biobanks (MIBI-TOF). Combining this technology with new reagents, statistical tools, and deep learning algorithms permitted us to generate the first comprehensive spatial representations of human tissue where the lineage and functional state of every cell was mapped and quantified. We have since used this capability to understand how immune function and tissue structure are coupled in cancer, infectious disease, and pregnancy. In these studies, we discovered spatial rulesets for predicting immune cell function and clinical outcome in pulmonary tuberculosis, ductal carcinoma in situ (DCIS), and triple negative-breast cancer (TNBC). Remarkably, we have found significant redundancy and conservation in these programs. This approach has revealed a shared ontology in pregnancy, tuberculosis granulomas, and metastatic cancer where innate immune suppression, stromal desmoplasia, and regulatory T-cells sustain a tolerogenic niche that deters cytotoxic T-cell infiltration. With this in mind, we are now working to create a universal spatial ontology of immune tolerance. Just as red, green, and blue can be mixed to create any color, we think the vast spectrum of tissue immune responses can be broken down into weighted combinations of a much smaller set of regulatory programs. Using complementary techniques for spatial transcriptomics and MALDI mass spectrometry imaging, we are expanding our spatial biology framework to map the spatial distribution of transcripts, lipids, and glycans. In doing so, our goal is to enable a new era of anatomic pathology where a single unified spatial representation can be used to discover regulatory pathways that can be targeted for diagnostic and therapeutic purposes.

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