864 Lesional immune cells in cutaneous acute graft-versus-host disease: A prospective cohort study

Abstract

Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lymphoproliferative disorders derived from skin-homing memory T cells. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common subtypes. Aberrant cytokine expression in the MF/SS tumor microenvironment (TME) is a major factor in disease pathogenesis and progression. We have previously shown that MF/SS malignant lymphocytes produce high levels of IL-13, which acts as an autocrine factor for tumor cells and suppresses tumor-cell immunosurveillance. Furthermore, our studies indicate that IL-13 synergizes with IL-4 in inducing SS cell growth and implicate IL-13 signaling via the Signal Transducer and Activator of Transcription-6 (STAT-6), an upstream mediator common to both IL-4 and IL-13 signaling. Significantly, we found high numbers of activated STAT-6 + cells in the affected skin of MF patients, particularly in advanced stages, implicating STAT-6 as a critical signaling mediator in MF/SS lymphocytes. To investigate the underlying molecular mechanism, we combined genome-wide transcriptional profiling with STAT-6 inhibition to identify the STAT-6-regulated genes in advanced-stage MF/ SS tumors. In malignant lymphocytes, we found that STAT-6 regulates the expression of genes associated with control of cell cycle progression and genomic stability, and its inhibition decreased proliferation. Furthermore, we showed that STAT-6 enhances expression of Th2 cytokines in malignant and reactive T cells by up-regulating the expression of GATA-3. Finally, we demonstrated that STAT-6 contributes to the pro-tumoral M2-like phenotype of macrophages in the TME of advanced-stage MF by up-regulating the expression of genes associated with immunosuppression, chemotaxis, and tumor matrix remodeling. Thus, STAT-6 contributes to MF/SS malignancy by several mechanisms including enhancing proliferation of tumor lymphocytes and promoting an immunosuppressive and pro-tumoral microenvironment that favors tumor growth and invasion.