Larsen Stine Kiær
Dan Med J. 2016 Jan;63(1):B5188.
This thesis describes the results from two published papers identifying spontaneous cellular immune responses against the transcription factors Foxp3 and Foxo3. The tumor microenvironment is infiltrated by cells that hinder effective tumor immunity from developing. Two of these cell types, which have been linked to a bad prognosis for patients, are regulatory T cells (Treg) and tolerogenic dendritic cells (DC). Tregs inhibit effector T cells from attacking the tumor through various mechanisms, including secreted factors and cell-to-cell contact. Tregs express the transcription factor Foxp3, which is necessary for their development and suppressive activities. Tolerogenic DCs participate in creating an environment in the tumor where effector T cells become tolerant towards the tumor instead of attacking it. The transcription factor Foxo3 was recently described to be highly expressed by tolerogenic DCs and to programme their tolerogenic influence. This thesis describes for the first time the existence of spontaneous cellular immune responses against peptides derived from Foxp3 and Foxo3. We have detected the presence of cytotoxic T cells that recognise these peptides in an HLA-A2 restricted manner in cancer patients and for Foxp3 in healthy donors as well. In addition, we have demonstrated that the Foxp3- and Foxo3-specific CTLs recognize Foxp3- and Foxo3-expressing cancer cell lines and importantly, suppressive immune cells, namely Tregs and in vitro generated DCs. Cancer immunotherapy is recently emerging as an important treatment modality improving the survival of selected patients. The current progress is largely owing to targeting of the immune suppressive milieu that is dominating the tumor microenvironment. This is being done through immune checkpoint blockade with CTLA-4 and PD-1/PD-L1 antibodies and through lymphodepleting conditioning of patients and ex vivo activation of TILs in adoptive cell transfer. Several strategies are being explored for depletion of Tregs and for modulation of Treg and DC suppressive activity, including CD25 antibodies and chemotherapy. The research presented in this thesis offer an alternative approach to targeting suppressive cells subsets, by activating the immune system against proteins expressed by these cell types.
本论文描述了两篇已发表论文的研究结果，这些研究确定了针对转录因子Foxp3和Foxo3的自发细胞免疫反应。肿瘤微环境中浸润着阻碍有效肿瘤免疫形成的细胞。其中两种与患者预后不良相关的细胞类型是调节性T细胞（Treg）和耐受性树突状细胞（DC）。Treg通过多种机制抑制效应T细胞攻击肿瘤，包括分泌因子和细胞间接触。Treg表达转录因子Foxp3，这对其发育和抑制活性至关重要。耐受性DC参与在肿瘤中创造一种环境，使效应T细胞对肿瘤产生耐受性而非攻击肿瘤。转录因子Foxo3最近被描述为在耐受性DC中高度表达，并赋予其耐受性影响。本论文首次描述了针对源自Foxp3和Foxo3的肽的自发细胞免疫反应的存在。我们在癌症患者中检测到了以HLA-A2限制性方式识别这些肽的细胞毒性T细胞，在健康供体中也检测到了针对Foxp3的细胞毒性T细胞。此外，我们证明了Foxp3和Foxo3特异性CTL识别表达Foxp3和Foxo3的癌细胞系，重要的是，还识别抑制性免疫细胞，即Treg和体外生成的DC。癌症免疫疗法最近正成为一种重要的治疗方式，可提高部分患者的生存率。目前的进展很大程度上归功于针对主导肿瘤微环境的免疫抑制环境的靶向治疗。这是通过使用CTLA-4和PD-1/PD-L1抗体进行免疫检查点阻断，以及通过对患者进行淋巴细胞清除预处理和在过继性细胞转移中对肿瘤浸润淋巴细胞进行体外激活来实现的。目前正在探索多种策略来清除Treg以及调节Treg和DC的抑制活性，包括使用CD25抗体和化疗。本论文中的研究提供了一种针对抑制性细胞亚群的替代方法，即通过激活免疫系统针对这些细胞类型表达的蛋白质。
