3D highly-multiplexed imaging and machine learning for immunoprofiling of human and murine tumors

About This Grant

SUMMARY/ABSTRACT Optical microscopy plays an essential role in cancer research by providing detailed information on single cell and organelle phenotypes. The recent development of spatial profiling approaches based on highly multiplexed tissue imaging makes it possible to perform detailed analysis of human and murine cells within a preserved tumor environment. This enables a precise analysis of tumor phenotypes and tumor-immune interaction, mechanism-of-action studies on approved and investigational drugs (as part of clinical trials) and promises to advance diagnostics for precision cancer care. As an NCI Research Specialist (Core-based), Clarence Yapp PhD will continue to support NCI-funded investigators and trainees involved in both classical and emerging microscopy applications and the use of machine learning/AI methods to convert complex images into quantitative single cell data. Yapp has extensive experience in microscopy and image analysis core facilities and currently serves as the Director of Microscopy and Computer Vision for the Laboratory of Systems Pharmacology (LSP) at Harvard Medical School (HMS). The LSP is an interdisciplinary multi-investigator laboratory that hosts about 100 core and affiliated faculty, students, and staff from multiple hospitals and universities in Eastern Massachusetts (seven institutions currently). It also provides instrumentation, software support, and methods development to several dozen other cancer biology groups in Boston and beyond. Yapp works at the interface between wet bench science, data analysis, and visualization, making him an unusually effective resource for a range of basic, translational, and clinical studies. He has served as co-chair of image- focused working groups for multiple NCI programs including the Cancer Systems Biology Consortium (CSBC), the Human Tumor Atlas Network (HTAN), and the Cellular Cancer Biology Imaging Research Program (CCBIR) and developed an international reputation for 3D tissue imaging. Yapp has published on a wide range of topics, often as first or senior author, with a current focus on imaging human tumors using multiplexed super-resolution 3D confocal and light sheet microscopy (LSFM). These 3D methods reveal single cell phenotypes and organelle morphologies not discernable in conventional 2D images and show that many multicellular structures are more extended and interconnected than hitherto thought. As a research specialist Yapp will: First, continue development and documentation of innovative 3D tissue imaging methods by working with trainees, faculty, and other LSP staff; Second, coordinate the development of software tools able to quantify the morphologies of individual cells and multi-cellular structures in 3D and use these to study immune cell states during cancer progression; Third, promote dissemination and uptake of 3D imaging methods by creating educational materials and disseminating these to microscopy core facility directors nationwide. Yapp’s research and training program will thereby provide essential support for Unit Director Prof. Sandro Santagata and two dozen other NCI-supported cancer biologists at HMS and beyond.