Laboratory of Cellular and Molecular Immunology, GIGA Research, University of Liège, 4000 Liège, Belgium.
Department of Pharmacotherapy and Pharmaceutics, Université Libre de Bruxelles (ULB), 1050 Bruxelles, Belgium.
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E9056-E9065. doi: 10.1073/pnas.1712883114. Epub 2017 Oct 10.
It has been shown that γδ T cells protect against the formation of squamous cell carcinoma (SCC) in several models. However, the role of γδ T cells in human papillomavirus (HPV)-associated uterine cervical SCC, the third-leading cause of death by cancer in women, is unknown. Here, we investigated the impact of γδ T cells in a transgenic mouse model of carcinogenesis induced by HPV16 oncoproteins. Surprisingly, γδ T cells promoted the development of HPV16 oncoprotein-induced lesions. HPV16 oncoproteins induced a decrease in epidermal Skint1 expression and the associated antitumor Vγ5 γδ T cells, which were replaced by γδ T-cell subsets (mainly Vγ6 γδCCR2CCR6) actively producing IL-17A. Consistent with a proangiogenic role, γδ T cells promoted the formation of blood vessels in the dermis underlying the HPV-induced lesions. In human cervical biopsies, IL-17A γδ T cells could only be observed at the cancer stage (SCC), where HPV oncoproteins are highly expressed, supporting the clinical relevance of our observations in mice. Overall, our results suggest that HPV16 oncoproteins induce a reorganization of the local epithelial-associated γδ T-cell subpopulations, thereby promoting angiogenesis and cancer development.
已经表明，γδ T 细胞在几种模型中可以预防鳞状细胞癌（SCC）的形成。然而，HPV 相关子宫颈 SCC（女性癌症死亡的第三大主要原因）中 γδ T 细胞的作用尚不清楚。在这里，我们研究了在 HPV16 致癌蛋白诱导的致癌转基因小鼠模型中 γδ T 细胞的影响。令人惊讶的是，γδ T 细胞促进了 HPV16 致癌蛋白诱导的病变的发展。HPV16 致癌蛋白诱导表皮 Skint1 表达和相关抗肿瘤 Vγ5 γδ T 细胞减少，被积极产生 IL-17A 的 γδ T 细胞亚群（主要是 Vγ6 γδCCR2CCR6）取代。与促血管生成作用一致，γδ T 细胞促进了 HPV 诱导病变下方真皮中血管的形成。在人宫颈活检中，仅在 HPV 致癌蛋白高度表达的癌症阶段（SCC）才能观察到 IL-17A γδ T 细胞，这支持了我们在小鼠中观察到的临床相关性。总体而言，我们的研究结果表明，HPV16 致癌蛋白诱导局部上皮相关 γδ T 细胞亚群的重新组织，从而促进血管生成和癌症发展。
