Abstract
Psoralen plus UVA (PUVA) is an effective therapy for mycosis fungoides (MF), the skin-limited variant of cutaneous T cell lymphoma (CTCL). In low-burden patients, PUVA reduced or eradicated malignant T cells and induced clonal expansion of CD8+ T cells associated with malignant T cell depletion. High-burden patients appeared to clinically improve but large numbers of malignant T cells persisted in skin. Clinical improvement was linked to turnover of benign T cell clones but not to malignant T cell reduction. Benign T cells were associated with the Th2-recruiting chemokine CCL18 before therapy and with the Th1-recruiting chemokines CXCL9, CXCL10, and CXCL11 after therapy, suggesting a switch from Th2 to Th1. Inflammation was correlated with OX40L and CD40L gene expression; immunostaining localized these receptors to CCL18-expressing c-Kit+ dendritic cells that clustered together with CD40+OX40+ benign and CD40+CD40L+ malignant T cells, creating a proinflammatory synapse in skin. Our data suggest that visible inflammation in CTCL results from the recruitment and activation of benign T cells by c-Kit+OX40L+CD40L+ dendritic cells and that this activation may provide tumorigenic signals. Targeting c-Kit, OX40, and CD40 signaling may be novel therapeutic avenues for the treatment of MF.
Highlights
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous collection of non-Hodgkin’s lymphomas derived from T cells tropic for the skin
plus ultraviolet A (UVA) (PUVA) is an effective therapy for mycosis fungoides (MF) that can eradicate malignant T cells in patients with low initial tumor burden
Clinical severity of disease was assessed in a single index lesion using the Composite Assessment of Index Lesion Severity (CAILS) scoring system and across the entire body surface area using the Modified Severity-Weighted Assessment Tool scoring system (Figure 1, A and B)
Summary
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous collection of non-Hodgkin’s lymphomas derived from T cells tropic for the skin. Unlike most nodal non-Hodgkin’s lymphomas, approximately 75% of primary cutaneous lymphomas are T cell derived. CTCL patients have inflammatory skin lesions infiltrated by both malignant and benign infiltrating T cells, and variable involvement of the blood, lymph nodes, and visceral organs. In mycosis fungoides (MF), the most common subtype of CTCL, malignant T cells are confined to inflammatory skin lesions [1]. Twenty percent of MF patients develop progressive, often lethal skin disease [4]. Even in patients with indolent MF, lymphomatous involvement of the skin is lifelong and disease is incurable in the absence of stem cell transplantation. A better understanding of the pathogenesis of MF is needed to develop therapies that can cure or halt progression of the disease
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