Arra Aditya, Lingel Holger, Kuropka Benno, Pick Jonas, Schnoeder Tina, Fischer Thomas, Freund Christian, Pierau Mandy, Brunner-Weinzierl Monika C
Department of Pediatrics, University Hospital, Health Campus Immunology, Infectiology and Inflammation, Otto-von-Guericke-University , Magdeburg, Germany.
Institut für Chemie und Biochemie, Protein Biochemistry Group, Freie Universität, Berlin, Germany; Mass Spectrometry Group, Leibniz-Institut für Molekulare Pharmakologie, Berlin, Germany.
Oncoimmunology. 2017 Jan 20;6(2):e1273300. doi: 10.1080/2162402X.2016.1273300. eCollection 2017.
As the blockade of inhibitory surface-molecules such as CTLA-4 on T cells has led to recent advances in antitumor immune therapy, there is great interest in identifying novel mechanisms of action of CD8 T cells to evoke effective cytotoxic antitumor responses. Using and models, we investigated the molecular pathways underlying the CTLA-4-mediated differentiation of IL-17-producing CD8 T cells (Tc17 cells) that strongly impairs cytotoxicity. Our studies demonstrate that Tc17 cells lacking CTLA-4 signaling have limited production of STAT3-target gene products such as IL-17, IL-21, IL-23R and RORγt. Upon re-stimulation with IL-12, these cells display fast downregulation of Tc17 hallmarks and acquire Tc1 characteristics such as IFNγ and TNF-α co-expression, which is known to correlate with tumor control. Indeed, upon adoptive transfer, these cells were highly efficient in the antigen-specific rejection of established OVA-expressing B16 melanoma . Mechanistically, in primary and re-stimulated Tc17 cells, STAT3 binding to the IL-17 promoter was strongly augmented by CTLA-4, associated with less binding of STAT5 and reduced relative activation of STAT1 which is known to block STAT3 activity. Inhibiting CTLA-4-induced STAT3 activity reverses enhancement of signature Tc17 gene products, rendering Tc17 cells susceptible to conversion to Tc1-like cells with enhanced cytotoxic potential. Thus, CTLA-4 critically shapes the characteristics of Tc17 cells by regulating relative STAT3 activation, which provides new perspectives to enhance cytotoxicity of antitumor responses.
由于对T细胞上诸如CTLA-4等抑制性表面分子的阻断已在抗肿瘤免疫治疗中取得了最新进展，因此人们对确定CD8 T细胞引发有效细胞毒性抗肿瘤反应的新作用机制产生了浓厚兴趣。利用[具体模型1]和[具体模型2]模型，我们研究了CTLA-4介导的产生IL-17的CD8 T细胞（Tc17细胞）分化的分子途径，这种分化会严重损害细胞毒性。我们的研究表明，缺乏CTLA-4信号的Tc17细胞产生的STAT3靶基因产物如IL-17、IL-21、IL-23R和RORγt有限。在用IL-12再次刺激后，这些细胞显示出Tc17特征的快速下调，并获得Tc1特征，如IFNγ和TNF-α共表达，已知这与肿瘤控制相关。事实上，在过继转移后，这些细胞在抗原特异性排斥已建立的表达OVA的B16黑色素瘤方面非常高效。从机制上讲，在原代和再次刺激的Tc17细胞中，CTLA-4强烈增强了STAT3与IL-17启动子的结合，同时STAT5的结合减少，STAT1的相对激活降低，已知STAT1会阻断STAT3的活性。抑制CTLA-4诱导的STAT3活性可逆转标志性Tc17基因产物的增强，使Tc17细胞易于转化为具有增强细胞毒性潜力的Tc1样细胞。因此，CTLA-4通过调节相对的STAT3激活来关键地塑造Tc17细胞的特征，这为增强抗肿瘤反应的细胞毒性提供了新的视角。
