Project 2: Spatial architecture of tumor-mediated immunosuppression
Beyond the internal genomic and epigenetic events that occur to drive a cell towards outright carcinogenesis and then metastasis, there co-exist the ordered events a cancer imposes on immune cells it encounters on its progression towards advanced disease. Induction of tolerance, avoidance of apoptosis, and even recruitment of the immune system to aid a tumor’s growth are all poorly understood processes. We propose to undertake deep phenotyping of the 2D and 3D architecture of tumour-lymph node micro-environment—wherein it is expected some of the initial phases of the tumor’s avoidance and recruitment mechanisms are implemented. How is the architecture of the immune environment disrupted in the face of tumor metastasis? Are their micro-communities (as defined by particular cell-cell interactions) whose presence or absence defines an outcome in progression of the tumor? To this end we have developed a technology (ABSeq) that enables us to sensitively and quantitatively image tumors with 60 markers per 3 hours (scalable to 480 in a time-dependent manner) with markers selected from a range of intracellular or surface epitopes (recognized by antibodies) or RNAs. The hypothesis is that an orchestrated corruption of immune surveillance is initiated by cancers as they progress, and that the micro-scale architecture of the lymph node (by way of which cells are talking to whom and what broader effects occur across the lymph node and beyond) is disrupted in a defined manner. A major aim of the research is to, with ABSeq, define the 2D and 3D architecture and communities of immune and cancer cells in draining lymph nodes from 2 cancers (melanoma and head and neck cancer) in murine models and with human samples. Databases of 2D and 3D microenvironments will be publicly created and mined for associations that define the architectural changes that occur as tumors progress and initiate tolerance.
Garry Nolan, PhD
Garry Nolan, Ph.D. is the Rachford and Carlota A. Harris Professor in the Department of Microbiology and Immunology at Stanford University School of Medicine. He trained with Leonard Herzenberg (for his Ph.D.) and Nobelist Dr. David Baltimore (for postdoctoral work for the first cloning/characterization of NF-kB p65/ RelA and the development of rapid retroviral production systems). He has published over 180 research articles and is the holder of 20 US patents, and has been honored as one of the top 25 inventors at Stanford University. Dr. Nolan is the first recipient of the Teal Innovator Award (2012) from the Department of Defense (a $3.3 million grant for advanced studies in ovarian cancer), the first recipient of an FDA BAAA, for “Bio-agent protection” grant, $3million, from the FDA for a “Cross-Species Immune System Reference”, and received the award for “Outstanding Research Achievement in 2011” from the Nature Publishing Group for his development of CyTOF applications in the immune system. Dr. Nolan has new efforts in the study of Ebola, having developed instrument platforms to deploy in the field in Africa to study Ebola samples safely with the need to transport them to overseas labs (funded by a new $3.5 million grant from the FDA).
Dr. Nolan is an outspoken proponent of translating public investment in basic research to serve public welfare. Dr. Nolan was the founder of Rigel Inc. (NASDAQ: RIGL), and Nodality, Inc. (a diagnostics development company), BINA (a genomics computational infrastructure company sold to Roche Diagnostics), and serves on the Boards of Directors of several companies as well as consults for other biotechnology companies. DVS Sciences, on which he was Chair of the Scientific Advisory Board, recently sold to Fluidigm for $207 million dollars (2014) on an investment of $14 million.
His areas of research include hematopoiesis, cancer and leukemia, autoimmunity and inflammation, and computational approaches for network and systems immunology. Dr. Nolan’s recent efforts are focused on a single cell analysis advance using a mass spectrometry-flow cytometry hybrid device, the socall “CyTOF” and the “Multiparameter Ion Beam Imager” (MIBI) developed by Dr. Mike Angelo in his lab (Dr. Angelo is now an Assistant Professor in the Dept of Pathology at Stanford). The approaches uses an advanced ion plasma source to determine the levels of tagged reagents bound to cells enabling a vast increase in the number of parameters that can be measured per cell either as flow cytometry devices (CyTOF) or imaging platforms for cancer (MIBI).Further efforts are being develop with another imaging platform termed CODEX that inexpensively converts fluorescence scopes to high dimensional imaging platforms.Dr. Nolan’s efforts are to enable a deeper understanding not only of normal immune function, trauma, pathogen infection, and other inflammatory events but also detailed substructures of leukemias and solid cancers which will enable wholly new understandings that will enable better management of disease and clinical outcomes.