Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214,USA.
J Immunol. 2011 Oct 15;187(8):4109-18. doi: 10.4049/jimmunol.1101136. Epub 2011 Sep 9.
Intratumoral delivery of IL-12 and GM-CSF induces local and systemic antitumor CD8(+) T cell activation and tumor kill. However, the effector response is transient and is rapidly countered by CD4(+) Foxp3(+) T suppressor cell expansion. To determine whether depletion of the pre-existing T suppressor cell pool prior to treatment could diminish posttherapy regulatory cell resurgence, FVBneuN mice bearing advanced spontaneous mammary tumors were treated with cyclophosphamide (CY) 1 d before IL-12/GM-CSF therapy. Administration of CY mediated a significant delay in the post-IL-12/GM-CSF T suppressor cell rebound, resulting in a 7-fold increase in the CD8(+) CTL/T suppressor cell ratio, a 3-fold enhancement of CTL cytotoxicity, and an extension of the effector window from 3 to 7 d. In long-term therapy studies, chronic chemoimmunotherapy promoted a dramatic enhancement of tumor regression, resulting in complete cure in 44% of the mice receiving CY plus IL-12/GM-CSF. Tumor eradication in the chronic therapy setting was associated with the ability to repeatedly rescue and maintain cytotoxic CD8(+) T cell activity. These findings demonstrated that chronic administration of CY in conjunction with immune therapy enhances the initial induction of antitumor T effector cells and, more importantly, sustains their cytotoxic activity over the long-term via persistent blockade of homeostatic counter-regulation.
瘤内递送白介素-12 和粒细胞-巨噬细胞集落刺激因子可诱导局部和全身抗肿瘤 CD8(+)T 细胞激活和肿瘤杀伤。然而，效应应答是短暂的，并且迅速被 CD4(+)Foxp3(+)T 抑制性细胞的扩增所抵消。为了确定在治疗前耗尽预先存在的 T 抑制性细胞池是否可以减少治疗后调节性细胞的复苏，用环磷酰胺（CY）预处理 FVBneuN 小鼠 1 天，然后用 IL-12/GM-CSF 治疗。CY 的给药导致 IL-12/GM-CSF 后 T 抑制性细胞反弹显著延迟，导致 CD8(+)CTL/T 抑制性细胞比增加 7 倍，CTL 细胞毒性增强 3 倍，并将效应窗从 3 天延长至 7 天。在长期治疗研究中，慢性化疗免疫治疗显著促进肿瘤消退，接受 CY 加 IL-12/GM-CSF 治疗的小鼠中有 44%完全治愈。在慢性治疗环境中消除肿瘤与反复挽救和维持细胞毒性 CD8(+)T 细胞活性的能力有关。这些发现表明，慢性 CY 给药联合免疫治疗可增强抗肿瘤 T 效应细胞的初始诱导，更重要的是，通过持续阻断同源性平衡调节来维持其长期的细胞毒性活性。
