Understanding pathogenesis: Apoptosis disruption may fuel formation of cutaneous lymphomas

November 1, 2008

New knowledge about the molecular pathogenesis of cutaneous lymphomas provides a basis for several new treatments under development, an expert says.

Key Points

International report - Dysregulation of the apoptotic process could be a key driver in the formation of cutaneous lymphomas, an expert says.

"Because we don't have any disease-specific molecular abnormalities in cutaneous T-cell lymphoma (CTCL), we assume that we don't understand the pathogenesis," says Sean J. Whittaker, M.D., director of molecular research, Skin Tumor Unit, St. John's Institute of Dermatology, London.

But in reality, Dr. Whittaker says, "We do have some clarity as to what the key molecular changes are, despite the fact that we still lack that key disease-specific molecular abnormality."

To date, the fact that researchers have been unable to develop long-term cultures - CTCL cells become relatively anergic when removed from the body - has been the major stumbling block in studying CTCL's molecular pathogenesis, Dr. Whittaker tells Dermatology Times.

However, he says, "There is evidence that certain growth factors, including interleukin (IL)-7 and IL-15, which may be keratinocyte-derived, are responsible for maintaining normal memory T cells in a population in a proliferative state as well."

The scenario in CTCL may be no different than what occurs in normal memory T cells, he says.

In fact, in vitro research has shown that if one co-cultures CTCL cells with dendritic cells, the establishment of long-term cultures can occur (Berger CL et al. Blood. 15 April 2002; 99(8):2929-2939), Dr. Whittaker says.

Researchers also are showing significant interest in the concept of regulatory T cells, which are critical cells in preventing autoimmune disease, Dr. Whittaker says.

"Because tumor cells in mycosis fungoides (MF) and Sézary syndrome (SS) can be CTLA-4 positive and CD25-positive," he says, "there's been interest in trying to define whether they have regulatory T-cell phenotype and function."

FOXP3

Additionally, many immunohistochemistry studies have looked at FOXP3 expression, a transcription factor expressed as a marker of regulatory T cells.

From these studies, he says, "It's clear that the number of FOXP3-positive tumor cells, or at least FOXP3-positive T cells in infiltrates of MF, is quite low."

A more recent study suggests this is especially true in early-stage disease, he says.

Researchers also know that Sézary cells can adopt a regulatory T-cell phenotype.

"This seems to be very heterogeneous," Dr. Whittaker says, "but the cells seem to lack the ability to functionally suppress autologous T cells, which suggests strongly that there is a defect in their ability to function as regulatory T cells, even if they do express a Trig phenotype."

Regarding regulatory T cells, Dr. Whittaker says, "It may be that the proportion of regulatory T cells in early stages of MF is higher than in later stage disease, and it's probably a good prognostic marker in CTCL and for other lymphomas."