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000300317 0247_ $$2doi$$a10.1136/jitc-2024-010352
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000300317 1001_ $$0P:(DE-He78)f1f0076fc72606659a5df2605acce91b$$aSun, Qian$$b0$$eFirst author$$udkfz
000300317 245__ $$aNeural crest-associated gene FOXD1 induces an immunosuppressive microenvironment by regulating myeloid-derived suppressor cells in melanoma.
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000300317 520__ $$aNeural crest-associated genes play pivotal roles in tumor initiation, progression, and the intricate dynamics of the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSC) within the TME are important in dampening T cell activity and contributing to resistance against immunotherapeutic interventions. The neural crest-associated gene Forkhead Box D1 (FOXD1) has been identified as an oncogenic factor that induces melanoma dedifferentiation and progression. However, the underlying mechanisms and the impact of FOXD1 on the antitumor immune response remain unclear.To investigate the impacts of FOXD1 on the melanoma microenvironment, we analyzed publicly available datasets from multiple platforms, including TNMplot, TIMER2.0, etc. In addition, FOXD1 was overexpressed (OE) or knocked down in melanoma cells to identify its biological functions in vitro and in vivo. Flow cytometry and arginase activity assay were used to analyze the phenotype and function of MDSC. Western blot, reverse transcription-PCR, or ELISA assays were employed to analyze the expression of FOXD1 and its downstream effectors. In vivo experiments were conducted to investigate the role of FOXD1 in melanoma progression and the influence on MDSC accumulation within the TME.We demonstrate that increased FOXD1 levels inversely correlated with melanoma responsiveness to immunotherapy. Ex-vivo analyses unveiled that monocytes, exposed to conditioned medium from FOXD1-OE melanoma cells, effectively suppressed T cell proliferation and upregulated the expression of programmed death-ligand 1 (PD-L1) and other immunosuppressive factors. FOXD1 was identified as a direct regulator of interleukin 6 (IL6) expression, which is pivotal for MDSC induction. Blocking IL6 reversed MDSC-associated immunosuppression. Additionally, miR-581, a potential negative regulator of FOXD1, attenuated the impact of FOXD1 on IL6 expression and MDSC differentiation. In vivo experiments demonstrated that tumors derived from FOXD1 OE melanoma cells contained a significantly higher frequency of PD-L1+ MDSC compared with controls, while FOXD1 knockdown resulted in reduced tumor growth and diminished MDSC accumulation.Our study elucidated a novel function of FOXD1 in melanoma pathogenesis, highlighting its role in orchestrating the immunosuppressive TME by promoting the generation of MDSC via IL6 upregulation.
000300317 536__ $$0G:(DE-HGF)POF4-311$$a311 - Zellbiologie und Tumorbiologie (POF4-311)$$cPOF4-311$$fPOF IV$$x0
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000300317 650_7 $$2Other$$aImmunosuppression
000300317 650_7 $$2Other$$aMyeloid-derived suppressor cell - MDSC
000300317 650_7 $$2Other$$aSkin Cancer
000300317 650_7 $$2Other$$aTumor microenvironment - TME
000300317 650_7 $$2NLM Chemicals$$aForkhead Transcription Factors
000300317 650_7 $$2NLM Chemicals$$aFOXD1 protein, human
000300317 650_2 $$2MeSH$$aMyeloid-Derived Suppressor Cells: immunology
000300317 650_2 $$2MeSH$$aMyeloid-Derived Suppressor Cells: metabolism
000300317 650_2 $$2MeSH$$aMelanoma: genetics
000300317 650_2 $$2MeSH$$aMelanoma: pathology
000300317 650_2 $$2MeSH$$aMelanoma: immunology
000300317 650_2 $$2MeSH$$aMelanoma: metabolism
000300317 650_2 $$2MeSH$$aHumans
000300317 650_2 $$2MeSH$$aAnimals
000300317 650_2 $$2MeSH$$aForkhead Transcription Factors: metabolism
000300317 650_2 $$2MeSH$$aForkhead Transcription Factors: genetics
000300317 650_2 $$2MeSH$$aTumor Microenvironment: immunology
000300317 650_2 $$2MeSH$$aMice
000300317 650_2 $$2MeSH$$aNeural Crest: metabolism
000300317 650_2 $$2MeSH$$aCell Line, Tumor
000300317 7001_ $$0P:(DE-He78)f3d19b02f83230d528305e528fcd72c8$$aWang, Nina$$b1$$udkfz
000300317 7001_ $$0P:(DE-He78)88a268b9173c651561385cddfdf819fa$$aPoelchen, Juliane$$b2
000300317 7001_ $$0P:(DE-He78)546bfa827219c21271966448a4321e61$$aPeter, Mareike$$b3
000300317 7001_ $$0P:(DE-He78)5f0b1c9863f44d0695555ee3c22b9758$$aNovak, Daniel$$b4$$udkfz
000300317 7001_ $$0P:(DE-He78)1784bfc87359b14c283e6b02cabca28d$$aÖzbay Kurt, Feyza Gül$$b5$$udkfz
000300317 7001_ $$0P:(DE-He78)d56d42ddfa25c8d79cba10aed608b0df$$aBitsch, Rebekka$$b6
000300317 7001_ $$0P:(DE-He78)09029e5d1361b4ff0c0e9ca28c5c9943$$aWu, Huizi$$b7
000300317 7001_ $$0P:(DE-He78)ada7e359a1f7451130dbc79595227bec$$aWang, Yiman$$b8
000300317 7001_ $$0P:(DE-HGF)0$$aPardo, Sandra$$b9
000300317 7001_ $$00009-0004-8843-9938$$aHan, Rui$$b10
000300317 7001_ $$aLiu, Shibo$$b11
000300317 7001_ $$aGong, Lidong$$b12
000300317 7001_ $$0P:(DE-He78)66623fe2fa2e29982369f4d828fec9bd$$aZhang, Yuxin$$b13$$udkfz
000300317 7001_ $$0P:(DE-He78)9512bd1a1d23a9812ab49fafcfa56ebf$$aWistuba-Hamprecht, Kilian$$b14$$udkfz
000300317 7001_ $$0P:(DE-He78)38be34240daf8b47325afc7910e77f7b$$aUmansky, Viktor$$b15$$udkfz
000300317 7001_ $$0P:(DE-He78)a229f7724466e7efadf4a1ace1ff8af3$$aUtikal, Jochen$$b16$$eLast author$$udkfz
000300317 773__ $$0PERI:(DE-600)2719863-7$$a10.1136/jitc-2024-010352$$gVol. 13, no. 4, p. e010352 -$$n4$$pe010352$$tJournal for ImmunoTherapy of Cancer$$v13$$x2051-1426$$y2025
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