Yale University Comprehensive Cancer Center and Department of Dermatology, New Haven, Connecticut 06520, USA
Address for correspondence: Richard L. Edelson, M.D., Deputy Dean for Clinical Affairs, Yale University School of Medicine, P.O. Box 208059, New Haven, Connecticut 06520-8059. Voice: 203-785-4091; fax: 203-785-7637.
richard.edelson{at}yale.edu
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.
