STAT3/5-dependent IL9 overexpression contributes to neoplastic cell survival in mycosis fungoides
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STAT3/5-dependent IL9 overexpression contributes to neoplastic cell survival in mycosis fungoides. / Vieyra-Garcia, Pablo A.; Wei, Tianling; Naym, David Gram; Fredholm, Simon; Fink-Puches, Regina; Cerroni, Lorenzo; Odum, Niels; O'Malley, John T.; Gniadecki, Robert; Wolf, Peter.
I: Clinical Cancer Research, Bind 22, Nr. 13, 07.2016, s. 3328-3339.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - STAT3/5-dependent IL9 overexpression contributes to neoplastic cell survival in mycosis fungoides
AU - Vieyra-Garcia, Pablo A.
AU - Wei, Tianling
AU - Naym, David Gram
AU - Fredholm, Simon
AU - Fink-Puches, Regina
AU - Cerroni, Lorenzo
AU - Odum, Niels
AU - O'Malley, John T.
AU - Gniadecki, Robert
AU - Wolf, Peter
PY - 2016/7
Y1 - 2016/7
N2 - Purpose: Sustained inflammation is a key feature of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). Resident IL9-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 patients with MF for the expression of IL9 and its regulators. To determine which cells were producing IL9, high-throughput sequencing was used to identify malignant clones and Vb-specific antibodies were employed to visualize malignant cells in histologic preparations. To explore the mechanism of IL9 secretion, we knocked down STAT3/5 and IRF4 by siRNA transfection in CTCL cell lines receiving psoralen+UVA (PUVA) ± anti-IL9 antibody. To further examine the role of IL9 in tumor development, the EL-4 T-cell lymphoma model was used in C57BL/6 mice. Results: Malignant and reactive T cells produce IL9 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 IL9- and IL9r-positive cells, as well as STAT3/5a and IRF4 expression in lesional skin. IL9 production was regulated by STAT3/5 and silencing of STAT5 or blockade of IL9 with neutralizing antibodies potentiated cell death after PUVA treatment in vitro. IL9-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 IL9 and its regulators are promising new targets for therapy development in mycosis fungoides.
AB - Purpose: Sustained inflammation is a key feature of mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL). Resident IL9-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 patients with MF for the expression of IL9 and its regulators. To determine which cells were producing IL9, high-throughput sequencing was used to identify malignant clones and Vb-specific antibodies were employed to visualize malignant cells in histologic preparations. To explore the mechanism of IL9 secretion, we knocked down STAT3/5 and IRF4 by siRNA transfection in CTCL cell lines receiving psoralen+UVA (PUVA) ± anti-IL9 antibody. To further examine the role of IL9 in tumor development, the EL-4 T-cell lymphoma model was used in C57BL/6 mice. Results: Malignant and reactive T cells produce IL9 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 IL9- and IL9r-positive cells, as well as STAT3/5a and IRF4 expression in lesional skin. IL9 production was regulated by STAT3/5 and silencing of STAT5 or blockade of IL9 with neutralizing antibodies potentiated cell death after PUVA treatment in vitro. IL9-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 IL9 and its regulators are promising new targets for therapy development in mycosis fungoides.
U2 - 10.1158/1078-0432.CCR-15-1784
DO - 10.1158/1078-0432.CCR-15-1784
M3 - Journal article
C2 - 26851186
AN - SCOPUS:84977074370
VL - 22
SP - 3328
EP - 3339
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 13
ER -
ID: 168909333