Li F, Guo Z, Yu H, Zhang X, Si T, Liu C, Yang X, Qi L
Neoplasma. 2014;61(6):659-71. doi: 10.4149/neo_2014_081.
Cryoablation combination therapy with blockade of the T-cell inhibitory receptor CTL-associated antigen-4 (CTLA-4) may augment the anti-tumor immune response (ATIR). It is crucial to determine the duration of ATIR after cryoablation and anti-CTLA-4 antibody therapy to determine the most appropriate treatment interval of therapy. To investigate the characteristics of ATIR induced by cryoablation and anti-CTLA-4 antibody therapy, we developed a prostate cancer model system to test the capacity of cryoablation and anti -CTLA-4 antibody to generate ATIR. Mice were randomly assigned to receive no treatment (group A), cryoablation only (group B), cryoablation plus anti-CTLA-4 antibody (group C), or anti-CTLA-4 antibody only (group D). We collected specimens on days 0, 7, 14 and 21 to study the ATIR through different techniques. Our results indicated that cryoablation induced ATIR and further enhanced this effect and reduced the number of distant metastases through combination with anti-CTLA-4 antibody. ATIR induced by cryoablation was achieved through decreasing regulatory T cell (Treg) number. The number of Tregs induced by cryoablation was lowest on day 14 but then returned to preoperative levels on day 21, indicating that ATIR induced by cryoablation was time-dependent. However, ATIR induced by anti-CTLA-4 antibody might be mainly achieved through influencing Treg function, which was exactly not by decreasing Treg number and still maintain its ATIR effect on day 21 after therapy. In conclusion, ATIR induced by cryoablation was achieved through decreasing Treg number and is time-dependent, whereas ATIR caused by anti-CTLA-4 antibody was achieved exactly not by decreasing Treg number and not time-dependent in the first 21 days after therapy.
冷冻消融联合阻断T细胞抑制性受体细胞毒性T淋巴细胞相关抗原4（CTLA-4）可能增强抗肿瘤免疫反应（ATIR）。确定冷冻消融和抗CTLA-4抗体治疗后ATIR的持续时间对于确定最合适的治疗间隔至关重要。为了研究冷冻消融和抗CTLA-4抗体治疗诱导的ATIR的特征，我们建立了一个前列腺癌模型系统，以测试冷冻消融和抗CTLA-4抗体产生ATIR的能力。将小鼠随机分为未治疗组（A组）、单纯冷冻消融组（B组）、冷冻消融加抗CTLA-4抗体组（C组）或单纯抗CTLA-4抗体组（D组）。我们在第0、7、14和21天收集标本，通过不同技术研究ATIR。我们的结果表明，冷冻消融诱导了ATIR，并通过与抗CTLA-4抗体联合进一步增强了这种效应，减少了远处转移灶的数量。冷冻消融诱导的ATIR是通过减少调节性T细胞（Treg）数量实现的。冷冻消融诱导的Treg数量在第14天最低，但在第21天恢复到术前水平，表明冷冻消融诱导的ATIR具有时间依赖性。然而，抗CTLA-4抗体诱导的ATIR可能主要是通过影响Treg功能实现的，这并非通过减少Treg数量，并且在治疗后第21天仍保持其ATIR效应。总之，冷冻消融诱导的ATIR是通过减少Treg数量实现的，具有时间依赖性，而抗CTLA-4抗体引起的ATIR并非通过减少Treg数量实现，且在治疗后的前21天不具有时间依赖性。
