CTCL is the most common adult malignancy of T lymphocytes, the white blood cells of the immune system. Finding CTCL triggering factors has been a major goal of Richard L. Edelson, M.D., Director of the Yale Cancer Center, and professor and chair of dermatology at Yale, since he and his colleagues at the National Cancer Institute first identified CTCL as a separate category of lymphoma thirty years ago.
The Yale research group reported that, like all T cells, the cancerous CTCL cells require antigenic stimuli delivered by specialized dendritic cells of the epidermis, referred to as Langerhans cells (LC), in order to replicate.
To determine the nature of the activating antigen, Carole Berger, a research scientist in dermatology set up a physiologic laboratory system mimicking the tight relationship in vivo between CTCL cells and LC. The research team considered three broad categories of antigen as the source of the signal: the protein products of tumor viruses, of mutated genes, and of normal but usually inactive genes.
The study reports that CTCL develops from a small subset of lymphocytes that are pre-programmed to respond to self-antigens exposed during normal cell death. As cells undergo the process of apoptosis, cryptic -- or masked -- antigens, are uncovered. Those newly available antigens are presented by LC directly to CTCL receptors, stimulating the malignant cells rapidly divide.
"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," said Edelson. "It may now be possible to identify specific antigens and target the malignant cells with selective poisons delivered through the vehicle of LC."
The study also showed that CTCL cells, after stimulation by LC, become functioning regulatory T (Treg) cells that suppress the immune responses of normal T cells to microbial agents. This may explain the susceptibility of patients with extensive CTCL to opportunistic infections.
"Through understanding T cell and dendritic cell interactions, we may gain the ability to manage a spectrum of maladies ranging from cancer to disorders of immune regulation," said Edelson. "Inhibiting Treg-cell generation may be useful for cancer immunotherapy and promoting Treg development may be useful to induce tolerance in autoimmune disease and transplantation,"
The research was supported by grants from the New York Cardiac Foundation and the National Institutes of Health and by the Yale Skin Disease Research Core Center.
Citation: Blood 105: 1640-1647 (February 2005)
Journal
Blood