The major focus of research in the Warren lab is the dissection of human antitumor immune responses at the cellular and molecular level. Identification and characterization of the immune effector cells and molecules that mediate tumor regression or elimination, and characterization of the relevant antigens recognized on tumor cells, will provide the foundation for the development of immune therapies that can manipulate these antitumor immune responses to clinical advantage.
Current effort is centered in several interrelated areas. The graft-versus-tumor (GVT) effect that occurs in recipients of allogeneic hematopoietic cell transplants is the one of the clearest examples of successful immunotherapy in humans. The GVT effect is mediated primarily by CD8+ and CD4+ T lymphocytes contained in or derived from the donor hematopoietic cell graft, and much of the lab’s current effort is dedicated to understanding the T cells that mediate the GVT effect and identifying their target antigens. A major class of these target antigens comprises minor histocompatibility antigens, which are short peptides encoded by polymorphic genes that are presented on the cell surface by MHC class I and II molecules. A related area of current research focus is the immunobiology of graft-versus-host disease (GVHD), with which the GVT effect is strongly associated, but which nonetheless causes significant morbidity and mortality after allogeneic hematopoietic cell transplantation; GVHD is one of the leading causes of treatment failure.
A third area of current research focus is the dissection of autologous immune responses against kidney and colon cancer. Kidney cancer is a common solid tumor in adults and is distinguished from many other solid tumors by its responsiveness to immune-based therapies. The identification of tumor-specific and tumor-associated antigens expressed on the surface of kidney cancer cells that could potentially be targeted with T cell-based immunotherapy is an active program in the lab. Colon cancer is another common solid tumor against which effective immune-based therapies might in the future be crafted. Recent studies in numerous labs have demonstrated that the adaptive immune system has a profound influence on the natural history of colon cancer, and that CD8+ T lymphocytes infiltrating the primary tumor are central mediators of this antitumor immune response. The Warren lab is actively investigating the antigenic specificity and effector functions of tumor-reactive CD8+ T lymphocytes infiltrating primary human colon tumors.
In addition, Dr. Warren's laboratory is collaborating with the labs of Drs. Harlan Robins and Christopher Carlson in the Public Health Sciences Division at the FHCRC on the development of techniques utilizing massively parallel DNA sequencing technologies to define more comprehensively than ever before possible the T cell receptor (TCR) repertoire of complex T lymphocyte populations. Comprehensive analysis of T cell populations at the clonal level using these new technologies will provide valuable insights into the immunobiology of tumors and autoimmune disease and will have important applications to the design and analysis of vaccines against infectious diseases.