Suzuki Eiji, Kapoor Veena, Jassar Arminder Singh, Kaiser Larry R, Albelda Steven M
Thoracic Oncology Research Laboratory, University of Pennsylvania, Philadelphia, PA 19104, USA.
Clin Cancer Res. 2005 Sep 15;11(18):6713-21. doi: 10.1158/1078-0432.CCR-05-0883.
Myeloid suppressor (Gr-1(+)/CD11b(+)) cells accumulate in the spleens of tumor-bearing mice where they contribute to immunosuppression by inhibiting the function of CD8(+) T cells and by promoting tumor angiogenesis. Elimination of these myeloid suppressor cells may thus significantly improve antitumor responses and enhance effects of cancer immunotherapy, although to date few practical options exist.
The effect of the chemotherapy drug gemcitabine on the number of (Gr-1(+)/CD11b(+)) cells in the spleens of animals bearing large tumors derived from five cancer lines grown in both C57Bl/6 and BALB/c mice was analyzed. Suppressive activity of splenocytes from gemcitabine-treated and control animals was measured in natural killer (NK) cell lysis and Winn assays. The impact of myeloid suppressor cell activity was determined in an immunogene therapy model using an adenovirus expressing IFN-beta.
This study shows that the chemotherapeutic drug gemcitabine, given at a dose similar to the equivalent dose used in patients, was able to dramatically and specifically reduce the number of myeloid suppressor cells found in the spleens of animals bearing large tumors with no significant reductions in CD4(+) T cells, CD8(+) T cells, NK cells, macrophages, or B cells. The loss of myeloid suppressor cells was accompanied by an increase in the antitumor activity of CD8(+) T cells and activated NK cells. Combining gemcitabine with cytokine immunogene therapy using IFN-beta markedly enhanced antitumor efficacy.
These results suggest that gemcitabine may be a practical strategy for the reduction of myeloid suppressor cells and should be evaluated in conjunction with a variety of immunotherapy approaches.
髓系抑制细胞（Gr-1(+)/CD11b(+)）在荷瘤小鼠脾脏中积聚，通过抑制CD8(+) T细胞功能和促进肿瘤血管生成来促成免疫抑制。因此，消除这些髓系抑制细胞可能会显著改善抗肿瘤反应并增强癌症免疫治疗效果，尽管迄今为止几乎没有实际可行的方法。
分析了化疗药物吉西他滨对在C57Bl/6和BALB/c小鼠体内生长的源自五种癌症细胞系的大型肿瘤动物脾脏中（Gr-1(+)/CD11b(+)）细胞数量的影响。在自然杀伤（NK）细胞裂解和Winn试验中测量了吉西他滨处理组和对照组动物脾细胞的抑制活性。在使用表达IFN-β的腺病毒的免疫基因治疗模型中确定了髓系抑制细胞活性的影响。
本研究表明，以与患者使用的等效剂量相似的剂量给予化疗药物吉西他滨，能够显著且特异性地减少荷大型肿瘤动物脾脏中髓系抑制细胞的数量，而CD4(+) T细胞、CD8(+) T细胞、NK细胞、巨噬细胞或B细胞数量无显著减少。髓系抑制细胞的减少伴随着CD8(+) T细胞和活化NK细胞抗肿瘤活性的增加。将吉西他滨与使用IFN-β的细胞因子免疫基因治疗相结合可显著增强抗肿瘤疗效。
这些结果表明，吉西他滨可能是减少髓系抑制细胞的一种实用策略，应结合多种免疫治疗方法进行评估。
