? Project 2: Spatial Architecture of Tumor-Mediated Immunosuppression Cancer progression is a disease of increasing disorder?yet a form of disorder with ordained stages of development. 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 the tumor-lymph node micro- environment in human cancer & murine model counterparts ?wherein it is thought that some of the initial phases of the tumor's avoidance and recruitment mechanisms are first implemented. How is the architecture of the immune environment disrupted in the face of tumor metastasis? Are their micro-communities changed (as defined by particular cell-cell interactions) whose presence or absence defines clinical outcomes during 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 3-5 hours (scalable to 480 in a time-dependent manner). These markers are 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. Understanding of this process will result in mechanistic and therapeutic insights that are unavailable by other analysis modalities. Databases of 2D and 3D microenvironments will be publicly created and mined for associations that define the architectural changes in draining lymph nodes that occur as tumors progress and initiate tolerance. Perturbations that include immunotherapies will be implemented on the murine models to determine the further architectural changes that occur post therapy. Together the information will provide a first ever deep profiling of every major immune cell subset in lymph nodes as they re-architect themselves during metastatic establishment.
|Spitzer, Matthew H; Carmi, Yaron; Reticker-Flynn, Nathan E et al. (2017) Systemic Immunity Is Required for Effective Cancer Immunotherapy. Cell 168:487-502.e15|
|Kenkel, Justin A; Tseng, William W; Davidson, Matthew G et al. (2017) An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer. Cancer Res 77:4158-4170|
|Bhattacharya, Nupur; Yuan, Robert; Prestwood, Tyler R et al. (2016) Normalizing Microbiota-Induced Retinoic Acid Deficiency Stimulates Protective CD8(+) T Cell-Mediated Immunity in Colorectal Cancer. Immunity 45:641-655|