Cutaneous T cell lymphoma: the helping hand of dendritic cells.
Since its introduction 25 years ago, cutaneous T cell lymphoma has become the preferred designation for clonal malignancies of those CD4 thymus-derived lymphocytes ("cutaneous T cells") that preferentially migrate to skin. The varied cutaneous clinical presentations, dependent on the specific features of the dominant subclones of the malignant lymphocytes, historically led to confusing descriptive terms (mycosis fungoides, Sézary syndrome, lymphoma cutis, leukemia cutis, reticulum cell sarcoma of the skin). Recognition that all of these clinical presentations are cancers of a single type of cell has permitted their unification under the single, clarified heading cutaneous T cell lymphoma, or CTCL. As a neoplastic amplification of the skin-homing T cells from which it is derived, CTCL's distinctive features can be explained. The triad of skin localization, remarkable avoidance of bone marrow, often even in the context of extremely high leukemic counts, and infiltration of perifollicular T cell zones of the lymph nodes and spleen reflect the migratory pathway and homing patterns of cutaneous T cells. The usually retained levels of serum immunoglobulins and the resulting capacity to defend against encapsulated bacteria, often even in advanced CTCL, are manifestations of the helper function of the malignant T cells-that is, their functional capacity to stimulate B lymphocytes to produce immunoglobulin in a polyclonal manner. In contrast, the often-extreme normal T cell deficits in advanced CTCL, equivalent to those of late-stage AIDS, probably resulting from the production of suppressive cytokines such as IL-10, cause susceptibility to a broad range of opportunistic infections, the most common direct cause of death. Pautrier microabscesses, the pathognomonic feature of epidermotropic early CTCL, hold the clues to the pathogenesis of the cancer. These intraepidermal collections of stimulated and proliferating malignant cells, adherent to the dendrites of intraepidermal dendritic antigen-presenting cells (Langerhans' cells [LCs]), indicate a dynamic communication between the two cell types. Since CTCL cells are derived from CD4 T cells, which normally receive signaling from dendritic cells (DCs) via presentation of antigenic peptides as part of class II major histocompatibility complexes to antigen-specific T cell receptors (TCRs), it seems likely that CTCL is a clonal proliferation of T cells responding to specific antigenic stimulation from LCs. This is supported by our recent finding that CTCL cells proliferate in vitro in response to TCR stimulation by autologous DCs, which have previously ingested and processed antigens from apoptotic autologous CTCL cells. In short, CTCL may be a malignancy of T cells stimulated to proliferate against its own tumor antigens. The most intriguing possibility is that a yet-unidentified transforming retrovirus, harbored by LCs, simultaneously attracts, stimulates, and transforms a single clone of antigen-specific cutaneous T cells. Longstanding disease-free remissions have been induced by transimmunization (via a photopheresis apparatus). This treatment, introduced more than a decade ago by our group and the first and still the only FDA-approved selective anticancer immunotherapy, has been performed more than 200,000 times worldwide on advanced CTCL, as well as in reversal/prevention of heart transplant rejection and treatment of graft-versus-host disease and selected autoimmune disorders. Transimmunization induces clinically relevant suppression, and occasionally elimination, of pathogenic T cell clones. The common denominator between these diverse groups of responding patients is the presence of clonally distinctive TCRs on the disease-causing malignant or autoaggressive T cell clones. In CTCL at least one source of tumor-specific antigens is derived from the clone-specific (idiotypic) segments of the TCR protein chains. In the photopheresis apparatus, two synergistic phenomena are initiated: induction of apoptosis of the CTCL cells and mass conversion of blood monocytes to DCs. The young DCs then ingest the apoptotic CTCL cells, process and present the CTCL antigens to responding anti-CTCL cytotoxic T cells, and stimulate clinically important CTCL suppression. Now that it is better understood, transimmunization may have much broader applications in other types of cancer as well.