Project 1: Murine modeling of tumor-mediated immunosuppression

We hypothesize that lymph node (LN) metastasis constitutes an essential step in the metastatic cascade of melanomas and head and neck tumors in that such metastases act locally upon the adaptive immune system within the nodes to induce tolerance to the tumor and that leukocytes recirculating from these nodes carry the tolerance to distant sites. Our objectives are to establish whether LN metastases induce perturbations in anti-tumor immunity and to identify the mechanisms of these perturbations. We will a) characterize differences in local and systemic immune responses to metastatic tumors; b) identify differential regulators of tolerance induction by metastatic cells through the use of genomic profiling; and c) identify the molecular mediators of metastatic tolerance induction in mice and humans. Through the use of serial in vivo passaging, we have developed a panel of syngeneic melanoma cell lines that exhibit enhanced LN metastatic potential. We will compare the activation states of these immune cells, cytokine profiles, T cell polarization, and cytolytic activity toward tumor cells using single cell proteomic methods (Project 2). Using cytokine profiling and RNA sequencing on the lines, we will apply computational systems biology approaches (Project 3) to identify the molecules relevant for induction of tolerance. If our hypothesis is proven correct that LN metastasis is an obligate step in the generation of systemic disease due to tolerance induction, targeting the molecules responsible for LN metastasis induced tolerance could prevent and treat metastatic disease.

Edgar Engleman, MD, PhD

Ed Engleman, M.D., Ph.D. is Professor of Pathology and of Medicine Immunology and Rheumatology). His laboratory studies the biology of immune cells and their roles in the pathogenesis of cancers and other life-threatening diseases. By applying new and more precise analytical tools for assessing this system in mice and humans, they have been successful at identifying disease-promoting immune abnormalities. By targeting the cells responsible for or affected by these abnormalities, they have succeeded in reversing the abnormalities and ameliorating the diseases they cause.

Dr Engleman’s lab has been particularly interested in the biology and functions of dendritic cells (DC), which are potent antigen presenting cells that can either induce or suppress immunity. Their first generation methods for isolating and arming human DC with tumor antigens provided the basis for the Sipuleucel-T vaccine that was approved by the FDA in 2010 for the treatment of metastatic prostate cancer. More recently, the lab developed a novel immunotherapeutic strategy that targets tumoral DC in vivo. In addition, they have been using newer technologies, including high dimensional single cell proteomic technology (CyTOF) and deep gene sequencing to investigate the immune system in cancer. A key goal is to identify and understand the key cellular and molecular mechanisms required for tumor elimination. The lab makes extensive use of mouse models for in depth mechanistic studies in addition to studying human samples.

In addition to cancer, the Engleman lab have been studying the role of immune cells in autoimmune diseases, metabolic diseases, graft versus host disease and transplantation tolerance. Recently, the group has developed novel tools for studying microglia in the brain and has begun to use these tools to analyze the role of these rare immune cells in chronic neurodegenerative disorders such as Alzheimer’s Disease, Parkinson’s Disease and amyotrophic lateral sclerosis (ALS). Preliminary findings in mouse models suggest that abnormal metabolism affecting these cells may contribute to the development of these disorders.