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We study 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, we have been successful at identifying disease-promoting immune abnormalities. By targeting the cells responsible for or affected by these abnormalities, we have succeeded in reversing the abnormalities and ameliorating the diseases they cause. We make extensive use of mouse models for in depth mechanistic studies, but we also use human tissues to confirm the clinical relevance of our findings. To pursue this work, we have been using newer multiplex imaging technologies and deep gene sequencing.We have been particularly interested in myeloid immune cells, including dendritic cells (DCs) and macrophages, that can either induce or suppress immunity. Our first generation methods for isolating and arming human myeloid cells with tumor antigens provided the basis for the first FDA-approved cell-based immunotherapy --- i.e., Sipuleucel-T (Provenge) that was approved in 2010 for the treatment of advanced prostate cancer. Subsequently, we developed a treatment that reprograms immunosuppressive myeloid cells in tumors into immunostimulatory cells that present tumor antigens to host T cells, resulting in potent anti-tumor immunity. This strategy entered clinical trials in late 2020 for the treatment of multiple cancers. Most recently, we discovered that tumor cells colonizing lymph nodes alter their gene expression to enable interactions with immune cells in the involved nodes, resulting in tumor-specific immune tolerance that, in turn, enables distant metastasis. This discovery formed the basis for an ongoing multi-laboratory effort to decipher the cellular and molecular mechanisms underlying tumor metastasis.In addition to cancer, we have been studying the role of immune cells in neurodegenerative disease, metabolic diseases, and organ transplant rejection. We helped to develop a therapy that utilizes radiation to lymphoid organs to induce immune tolerance, enabling patients who receive organ transplants to retain those organs life-long without the need for immunosuppressive drugs. This therapy is now in advanced clinical trials in kidney transplant patients. The key to the success of this therapy appears to be the selective activation of tolerogenic myeloid immune cells. Our evidence suggests that the same cells function normally to prevent autoimmunity in healthy individuals but are hijacked by cancers to enable their escape from the host immune system. Once we fully understand this mechanism, which is independent of known checkpoint mechanisms, we believe there is the potential to manipulate it for the treatment of many diseases, including cancers and autoimmune disorders.