Current Research and Scholarly Interests
For the past 40 years my research has been directed at discovering ways to manipulate the immune system for the treatment and prevention of life-threatening diseases. At the start of my career, I generated the first monoclonal antibodies to human T lymphocytes, including anti-CD4 and anti-CD8, enabling me and others to isolate these cells and analyze their functions. In addition to these fundamental studies, I used the antibodies to develop a screening test for blood donors prior to the discovery of HIV, and later I used them to study the role of CD4 in HIV infection. Thereafter, I began a decades-long investigation into myeloid cell biology, focusing initially on dendritic cells (DCs). My group was the first to develop a method for isolating and arming human dendritic cells and evaluate their ability to induce anti-tumor immunity in cancer patients. Our work led to the development of the first immune cell therapy, Sipuleucel-T (Provenge), which was approved by the FDA in 2010 for the treatment of advanced prostate cancer. This accomplishment paved the way to a new era in which immune cell therapies have become standard treatments for several cancers. In the past decade, my research has been aimed at understanding the cellular and molecular basis of peripheral immune tolerance in health and disease. This effort led to the discovery that tumor cells that invade lymph nodes (LNs) alter LN-resident immune cells, resulting in the generation of tumor-specific Tregs that disseminate throughout the host and promote distant metastasis. Recently, we discovered that erythropoietin (Epo)-mediated activation of its receptor (EpoR) on macrophages and Type 1 DCs causes these cells to become tolerogenic and suppress anti-cancer immunity through their induction of antigen-specific Tregs and inhibition of CD8 cytotoxic T cells. This discovery was enabled by methods we developed for analyzing the immune response systemwide and our generation of novel mouse models of cancer that mimic their human counterparts in their driver mutations, growth characteristics and immune profiles. Beyond my research contributions, I am proud of having trained more than 100 graduate and postdoctoral students, many of whom have gone on to distinguished academic careers. Examples include Miriam Merad (Mount Sinai School of Medicine), Lawrence Fong (Fred Hutchinson Cancer Center), Matthew Spitzer (University of California, San Francisco), Daniel Winer (University of Toronto), Jeffrey Lifson (Frederick National Laboratory) and Nathan Reticker-Flynn (Stanford University).
