Ortner Daniela, Tripp Christoph H, Komenda Kerstin, Dubrac Sandrine, Zelger Bernhard, Hermann Martin, Doppler Wolfgang, Tymoszuk Piotr Z, Boon Louis, Clausen Björn E, Stoitzner Patrizia
Department of Dermatology, Venereology and Allergology, Medical University of Innsbruck , Innsbruck, Austria.
Department of Anesthesiology and Intensive Care Medicine, Medical University of Innsbruck , Innsbruck, Austria.
Oncoimmunology. 2016 Nov 18;6(2):e1260215. doi: 10.1080/2162402X.2016.1260215. eCollection 2017.
Tissue immunosurveillance is an important mechanism to prevent cancer. Skin treatment with the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), followed by the tumor promoter 12-O-tetra-decanoyl-phorbol-13-acetate (TPA), is an established murine model for squamous cell carcinoma (SCC). However, the innate immunological events occurring during the initiation of chemical carcinogenesis with DMBA remain elusive. Here, we discovered that natural killer (NK) cells and Langerhans cells (LC) cooperate to impair this oncogenic process in murine skin. The depletion of NK cells or LC caused an accumulation of DNA-damaged, natural killer group 2D-ligand (NKG2D-L) expressing keratinocytes and accelerated tumor growth. Notably, the secretion of TNFα mainly by LC promoted the recruitment of NK cells into the epidermis. Indeed, the TNFα-induced chemokines CCL2 and CXCL10 directed NK cells to DMBA-treated epidermis. Our findings reveal a novel mechanism how innate immune cells cooperate in the inhibition of cutaneous chemical carcinogenesis.
组织免疫监视是预防癌症的重要机制。用致癌物7,12-二甲基苯并(a)蒽（DMBA）处理皮肤，随后使用肿瘤促进剂12-O-十四烷酰佛波醇-13-乙酸酯（TPA），是一种已确立的鳞状细胞癌（SCC）小鼠模型。然而，在用DMBA进行化学致癌起始过程中发生的先天性免疫事件仍然不清楚。在这里，我们发现自然杀伤（NK）细胞和朗格汉斯细胞（LC）协同作用以损害小鼠皮肤中的这种致癌过程。NK细胞或LC的耗竭导致表达DNA损伤的自然杀伤细胞组2D配体（NKG2D-L）的角质形成细胞积累并加速肿瘤生长。值得注意的是，主要由LC分泌的TNFα促进了NK细胞向表皮的募集。事实上，TNFα诱导的趋化因子CCL2和CXCL10将NK细胞导向DMBA处理的表皮。我们的研究结果揭示了一种先天性免疫细胞如何协同抑制皮肤化学致癌作用的新机制。
