Center for Cancer Immune Therapy (CCIT); Department of Hematology; Copenhagen University Hospital ; Herlev ; Herlev, Denmark ; These authors contributed equally to this work.
Center for Cancer Immune Therapy (CCIT); Department of Hematology; Copenhagen University Hospital ; Herlev ; Herlev, Denmark.
Oncoimmunology. 2014 Nov 14;3(8):e953411. doi: 10.4161/21624011.2014.953411. eCollection 2014.
In the present study, we describe forkhead box O3 (FOXO3)-specific, cytotoxic CD8 T cells existent among peripheral-blood mononuclear cells (PBMCs) of cancer patients. FOXO3 immunogenicity appears specific, as we did not detect reactivity toward FOXO3 among T cells in healthy individuals. FOXO3 may naturally serve as a target antigen for tumor-reactive T cells as it is frequently over-expressed in cancer cells. In addition, expression of FOXO3 plays a critical role in immunosuppression mediated by tumor-associated dendritic cells (TADCs). Indeed, FOXO3-specific cytotoxic T lymphocytes (CTLs) were able to specifically recognize and kill both FOXO3-expressing cancer cells as well as dendritic cells. Thus, FOXO3 was processed and presented by HLA-A2 on the cell surface of both immune cells and cancer cells. As FOXO3 programs TADCs to become tolerogenic, FOXO3 signaling thereby comprises a significant immunosuppressive mechanism, such that FOXO3 targeting by means of specific T cells is an attractive clinical therapy to boost anticancer immunity. In addition, the natural occurrence of FOXO3-specific CTLs in the periphery suggests that these T cells hold a function in the complex network of immune regulation in cancer patients.
在本研究中，我们描述了存在于癌症患者外周血单核细胞（PBMC）中的叉头框蛋白 O3（FOXO3）特异性细胞毒性 CD8 T 细胞。FOXO3 的免疫原性似乎是特异性的，因为我们在健康个体的 T 细胞中没有检测到针对 FOXO3 的反应。FOXO3 可能自然成为肿瘤反应性 T 细胞的靶抗原，因为它在癌细胞中经常过度表达。此外，FOXO3 的表达在肿瘤相关树突状细胞（TADC）介导的免疫抑制中发挥关键作用。事实上，FOXO3 特异性细胞毒性 T 淋巴细胞（CTL）能够特异性识别和杀死表达 FOXO3 的癌细胞和树突状细胞。因此，FOXO3 由 HLA-A2 在免疫细胞和癌细胞的细胞表面进行加工和呈递。由于 FOXO3 将 TADC 编程为耐受性，因此 FOXO3 信号转导构成了一种重要的免疫抑制机制，使得通过特异性 T 细胞靶向 FOXO3 成为增强抗癌免疫的一种有吸引力的临床治疗方法。此外，FOXO3 特异性 CTL 在周围组织中的自然发生表明这些 T 细胞在癌症患者复杂的免疫调节网络中具有功能。
