Matthews Kate E, Hermans Ian F, Roberts Joanna M, Ching Lai-Ming, Ronchese Franca
Malaghan Institute of Medical Research, Wellington, New Zealand.
Immunol Cell Biol. 2006 Aug;84(4):383-9. doi: 10.1111/j.1440-1711.2006.01448.x.
The chemotherapeutic drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA) inhibits intratumoural blood flow, causing hypoxia, haemorrhagic necrosis, vascular collapse and tumour cell death. Production of TNF-alpha and IFN is also induced, causing local inflammation and activation of immune cells including CD8+ T cells. We used the tumour cell line LL-LCMV, which expresses the gp33 epitope of lymphocytic choriomeningitis virus in a non-immunogenic form, to investigate whether tumour cell death caused by treatment with DMXAA may improve the success of tumour immunotherapy mediated by CD8+ T cells. Treatment with DMXAA was effective at reducing the size of LL-LCMV tumours. However, compared to normal mice, tumour reduction was no more marked or sustained in mice carrying high numbers of naive, tumour-specific CD8+ T cells. The antitumour effect of activated CD8+ T cells was also not affected by DMXAA treatment. Tumour-specific CD8+ T cells activated in vivo by immunization with dendritic cells and specific tumour peptide antigen, or generated in vitro and adoptively transferred into tumour-bearing mice by i.v. injection, did not improve or sustain the reduction in tumour size induced by DMXAA treatment. We conclude that the presence of high numbers of naive CD8+ T cells, or immunotherapies leading to CD8+ T-cell activation, do not synergize with the tumour cell death and local inflammation induced by DMXAA treatment. It is possible that this lack of synergism may result from both treatments inducing activation of CD8+ T cells and that treatments that activate different populations of immune cells may achieve better success.
化疗药物5,6-二甲基呫吨酮-4-乙酸（DMXAA）可抑制肿瘤内血流，导致缺氧、出血性坏死、血管塌陷和肿瘤细胞死亡。同时还可诱导肿瘤坏死因子-α（TNF-α）和干扰素（IFN）的产生，引发局部炎症并激活包括CD8⁺T细胞在内的免疫细胞。我们使用了肿瘤细胞系LL-LCMV，该细胞系以非免疫原性形式表达淋巴细胞性脉络丛脑膜炎病毒的gp33表位，以研究DMXAA治疗引起的肿瘤细胞死亡是否可提高由CD8⁺T细胞介导的肿瘤免疫治疗的成功率。DMXAA治疗可有效减小LL-LCMV肿瘤的大小。然而，与正常小鼠相比，在携带大量初始的、肿瘤特异性CD8⁺T细胞的小鼠中，肿瘤缩小情况并无更显著或持续。活化的CD8⁺T细胞的抗肿瘤作用也不受DMXAA治疗的影响。通过树突状细胞和特异性肿瘤肽抗原免疫在体内活化的肿瘤特异性CD8⁺T细胞，或在体外产生并通过静脉注射过继转移至荷瘤小鼠体内的肿瘤特异性CD8⁺T细胞，均未改善或维持DMXAA治疗诱导的肿瘤大小缩小。我们得出结论，大量初始CD8⁺T细胞的存在，或导致CD8⁺T细胞活化的免疫治疗，不会与DMXAA治疗诱导的肿瘤细胞死亡和局部炎症产生协同作用。这种缺乏协同作用可能是由于两种治疗均诱导CD8⁺T细胞活化，并且激活不同免疫细胞群体的治疗可能会取得更好的效果。
