Outsmarting CTCL Cells by Decoding the Language They Speak

摘要

Since the term “Cutaneous T Cell Lymphoma” (CTCL) was introduced in 1974, investigation of the biology of the malignant T cells has contributed heavily to understanding of the clinically important biology of benign and neoplastic T cells. Availability of large numbers of clonal skin-homing CTCL cells facilitated the discovery of T cell-specific monoclonal antibodies and identification of “helper-T cells.” Tight linkage between the biology and clinical manifestations of CTCL cells has enabled major, and accelerating, scientific and practical advances. CTCL cells are now well defined by their distinctive features: membrane molecules which direct them to the skin; growth dependency on signaling from immature dendritic antigen presenting cells; origin from the large set of normal “cutaneous T cells” which recirculate between skin and blood; differentiation markers controlling the way they interact with antigen presenting cells, maintain memory for their cognate antigen and regulate normal T cells (CD4/CD45Ro/Treg); secretion of a Th2 set of cytokines; and surface expression of clinically targetable tumor distinctive antigens. CTCL provided the point of entry for now widely used biologically-based therapies: anti-lymphocyte antibodies to treat malignancies; cellular immunotherapy for cancer (Extracorporeal Photochemotherapy); IL2-diphtheria toxin fusion agent (Ontac); anti-cancer retinoid (Targretin); and anti-cancer inhibitors of histone deacetylase. On this rich foundation, we are now poised to resolve a next set of major questions. What are the skin-localized antigens that stimulate memory “cutaneous T cells” to clonally expand, prior to their malignant transformation? How can we best exploit the critical growth requirements and antigenicity of CTCL cells to develop even better therapies? Can we ultimately outsmart CTCL cells by interrupting their capacity to receive the growth stimulatory signals that they require to grow and spread?