Outsmarting Cutaneous T-Cell Lymphoma Cells by Decoding the Language They Speak: Focusing Past and Present Insights on Future Prospects

摘要

After the term "cutaneous T-cell lymphoma" (CTCL) was introduced in 1974, investigation of the biology of the malignant T cells has contributed heavily to an understanding of the clinically important biology of benign and neoplastic T cells. The availability of large numbers of clonal skin-homing CTCL cells facilitated the discovery of T-cell-specific monoclonal antibodies (MoAbs) 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. Cutaneous T-cell lymphoma cells are now well defined by their distinctive features: membrane molecules that 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" that recirculate between skin and blood; differentiation markers that control 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. Cutaneous T-cell lymphoma provided the point of entry for now widely used biologically based therapies: antilymphocyte antibodies to treat malignancies; cellular immunotherapy for cancer (extracor-poreal photochemotherapy); IL-2-diphtheria toxin fusion agent (Ontak~R [denileukin diftitox]; Eisai Inc.; Woodcliff Lake, NJ); anti-cancer retinoid (bexarotene); and anticancer inhibitors of histone deacetylase. On this rich foundation, we are now poised to resolve the next set of major questions: What are the skin-localized antigens that stimulate clonal expansion of memory cutaneous T cells before their malignant transformations? How can we best exploit the critical growth requirements and antigenicity of CTCL cells to develop better therapies? Can we ultimately outsmart CTCL cells by interrupting their capacity to receiv