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The Journal of investigative dermatology. 2025 Apr 9:S0022-202X(25)00404-X. doi: 10.1016/j.jid.2025.02.155 Q15.92024

Tolerogenic monocyte-derived langerhans cells promote melanoma progression and immunotherapy resistance through AhR-COX2 activation

单核细胞来源的朗格汉斯细胞通过AhR-COX2激活促进黑色素瘤进展和免疫治疗抵抗 翻译改进

Liyun Dong  1, Naming Wu  1, Zhen Cai  1, Shiyi Yan  1, Juan Pan  2, Liu Yang  1, Jinjin Zhu  1, Yujue Wang  1, Jun Li  3, Juan Tao  4

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作者单位

  • 1 Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Engineering Research Center of Skin Disease Theranostics and Health, Wuhan, Hubei, China.
  • 2 Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 3 Department of Dermatology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: goldcoindaniel@163.com.
  • 4 Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Engineering Research Center of Skin Disease Theranostics and Health, Wuhan, Hubei, China. Electronic address: juantao@hust.edu.cn.
  • DOI: 10.1016/j.jid.2025.02.155 PMID: 40216154

    摘要 中英对照阅读

    Langerhans cells (LCs), as epidermal-resident antigen-presenting cells, are among the first to encounter early carcinogenic changes in the skin, such as those seen in melanoma. During inflammation or cancer, circulating monocytes are recruited into the epidermis, replacing resident LCs (rLCs) that have migrated to draining lymph nodes. However, the specific roles of LC subsets in the progression of melanoma remain unclear. Here, we observed a decrease in rLCs and an increase in monocyte-derived LCs (moLCs) within melanoma tumor tissues as the disease progressed. Notably, the frequency of moLCs was higher in patients with anti-PD-1 therapy-resistant melanoma than in those responsive to the therapy. Using muLangerin-DTR transgenic and moLC-specific knockout mouse models, we demonstrated that the depletion of rLCs accelerated melanoma growth, whereas the depletion of moLCs suppressed tumor progression. Mechanistically, moLCs exhibited elevated expression of COX2-related genes compared to rLCs. TGF-β was found to activate aryl hydrocarbon receptor (AhR)-COX2 signaling in moLCs, leading to increased production of PGE2 and expression of PD-L1, which collectively contributed to the immunosuppressive effects of moLCs on CD8+CTLs. In summary, our findings highlight the functional heterogeneity of LC subsets in melanoma progression, offering deeper insights into LC biology and potential therapeutic strategies.

    Keywords: Immunity; Melanoma; TGF-β; moLC; rLC.

    Keywords:melanoma progression; immunotherapy resistance; ahr-cox2 activation

    郎格汉斯细胞(LCs)作为表皮驻留的抗原呈递细胞,在皮肤早期致癌变化中,如黑色素瘤,最先接触到这些变化。在炎症或癌症的情况下,循环中的单核细胞会被招募到表皮,替换已经迁移到引流淋巴结的居民郎格汉斯细胞(rLCs)。然而,郎格汉斯细胞亚群在黑色素瘤进展中的特定作用尚不清楚。在这里,我们观察到随着疾病的发展,黑色素瘤肿瘤组织中rLC数量减少而moLC数量增加。值得注意的是,在对anti-PD-1治疗无反应的患者中,moLC的比例高于对该疗法有反应的患者。使用muLangerin-DTR转基因和moLC特异性敲除小鼠模型,我们证明了rLCs的耗竭加速了黑色素瘤的增长,而moLCs的耗竭则抑制了肿瘤的发展。机制上,与rLC相比,moLC显示出了COX2相关基因表达升高的现象。TGF-β被发现激活了moLC中的芳烃受体(AhR)-COX2信号通路,导致PGE2产量增加和PD-L1的表达升高,这些共同促进了moLC对CD8+T细胞的免疫抑制效应。总之,我们的研究强调了郎格汉斯细胞亚群在黑色素瘤进展中的功能异质性,并为理解郎格汉斯生物学及潜在治疗策略提供了更深入的认识。

    关键词: 免疫;黑色素瘤;TGF-β;moLC;rLC。

    关键词:黑色素瘤进展; 免疫治疗抵抗; AHR-COX2激活

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    Copyright © The Journal of investigative dermatology. 中文内容为AI机器翻译,仅供参考!

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    期刊名:Journal of investigative dermatology

    缩写:J INVEST DERMATOL

    ISSN:0022-202X

    e-ISSN:1523-1747

    IF/分区:5.9/Q1

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    Tolerogenic monocyte-derived langerhans cells promote melanoma progression and immunotherapy resistance through AhR-COX2 activation