Source of Molecular Triggers in Cutaneous T Cell Lymphoma Identified
For Immediate Release
Date: 2/21/05
Contact: Renee Gaudette (203) 785-2143
In a scientific study published in the current issue of Blood, the official journal of the American Society of Hematology, Carole Berger, PhD, Richard Edelson, MD, and their colleagues identified the source of the molecular triggers which stimulate Cutaneous T Cell Lymphoma (CTCL) cells to clonally expand into large populations of malignant lymphocytes. CTCL is the most common adult malignancy of T lymphocytes, the white blood cells that normally play central roles in the function of the immune system. Identification of these CTCL triggering factors has been a principal goal of Dr. Edelson, Director of Yale Cancer Center, since he and his colleagues at the National Cancer Institute first identified CTCL as an individual category of lymphoma thirty years ago.
The Yale research group had recently reported that, like the normal T cells from which the cancer develops, CTCL cells require stimuli from specialized immature dendritic cells (DC) of the epidermis, referred to as Langerhans cells (LC), in order to replicate. That novel finding had become possible because of Dr. Berger's discovery of a physiologic laboratory system, mimicking the in vivo relationship between CTCL cells and LC. Since the LC signaled CTCL cell replication through presentation of immunogenic molecules (antigens) to the CTCL cell selective T cell receptor, it became important to determine the source of the relevant antigen. Three broad sources were considered candidates: protein products of tumor viruses, mutated genes, and normally quiescent genes.
In the current study, the researchers report that cryptic antigens, uncovered during the apoptotic process by which cells normally die, are presented by LC directly to CTCL receptors, allowing the malignant cells to make many copies of themselves. The findings are most consistent with the premise that CTCL develops from a small subset of T lymphocytes, which are genetically preprogrammed to respond to self-antigens exposed during normal cell death.
“This finding has broad implications for the understanding, diagnosis, and treatment of CTCL, as well as potentially contributing to the investigation of other types of lymphomas. With this new lead, it may now become possible to identify the particular antigen(s), which stimulate the CTCL cell multiplication and then target the malignant cells with selective poisons delivered through the vehicle of LC,” Dr. Edelson said.
The study also revealed that CTCL cells, after growth signaling by LC, become functional regulatory T cells (Tregs), which suppress normal T cell immune responses to microbial agents. This feature appears to explain the susceptibility of patients with extensive CTCL to opportunistic infections. Since the CTCL Tregs suppress normal T cell function through secretion of the inhibitory molecule CTLA-4, clinical trials of available anti-CTLA-4 monoclonal antibodies are under consideration.