STAT3/5 dependent IL-9 overexpression contributes to neoplastic cell survival in mycosis fungoides

Purpose: Sustained inflammation is a key feature of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). Resident IL-9-producing T- cells have been found in skin infections and certain inflammatory skin diseases but their role in MF is currently unknown. Experimental Design: We analyzed lesional skin from MF patients for expression of IL-9 and its regulators. To determine which cells were producing IL-9, high-throughput sequencing was used to identify malignant clones and Vb specific antibodies were employed to visualize malignant cells in histological preparations. To explore the mechanism of IL-9 secretion, we knocked down STAT3/5 and IRF4 by siRNA transfection in CTCL cell lines receiving psoralen+UVA (PUVA) +/-anti-IL-9 antibody. To further examine the role of IL-9 in tumor development, the EL-4 T-cell lymphoma model was used in C57BL/6 mice. Results: Malignant and reactive T-cells produce IL-9 in lesional skin. Expression of the Th9 transcription factor IRF4 in malignant cells was heterogeneous whereas reactive T- cells expressed it uniformly. PUVA or UVB phototherapy diminished the frequencies of IL-9- and IL-9r-positive cells, as well as STAT3/5a and IRF4 expression in lesional skin. IL-9 production was regulated by STAT3/5 and silencing of STAT5 or blockade of IL-9 with neutralizing antibodies potentiated cell death after PUVA in vitro. IL-9 depleted mice exhibited a reduction of tumor growth, higher frequencies of regulatory T-cells, and activated CD4 and CD8 T lymphocytes. Conclusions: Our results suggest that IL-9 and its regulators are promising new targets for therapy development in MF.

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