Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice
Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice
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DOI：
10.1016/j.intimp.2009.03.015
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发表时间：
2009-07-01
影响因子：
5.6
通讯作者：
Bear, Harry D.
中科院分区：
文献类型：
--
作者：
Le, Hanh K.;Graham, Laura;Bear, Harry D.
骨髓源性抑制细胞（MDSCs）在4T1乳腺癌小鼠体内积累，并通过抑制T细胞免疫对过继免疫治疗（AIT）的成功形成障碍。本研究中，我们研究了吉西他滨（GEM）对MDSCs的抑制作用。一种可能有良好免疫作用的化疗药物。BALB/c小鼠接种4T1乳腺癌细胞，并在肿瘤接种后5天开始每周1次（早期GEM）或在第2025天进行单剂量（晚期GEM）治疗。分离脾脏单核细胞，体外活化，扩增，肿瘤抗原刺激。然后将T细胞用于AIT治疗荷瘤小鼠。早期GEM治疗4T1荷瘤小鼠可显著抑制肿瘤生长，减少脾肿大，显著降低脾脏内MDSC比例。通过抑制晚期GEM治疗后24和48天采集的脾脏、骨髓和血液中的MDSCs，尽管肿瘤负荷没有显著减少，但证明了直接作用的支持。有趣的是，用GEM治疗荷瘤小鼠增强了脾脏T细胞的体外扩增，并增加了ifn - γ分泌，以响应肿瘤抗原的刺激。然而，尽管gem介导的MDSC抑制抑制，晚期肿瘤小鼠的脾T细胞在体内对已建立的肿瘤无效。本研究为GEM在4T1荷瘤小鼠中直接抑制MDSCs和直接减轻肿瘤负荷提供了支持。GEM治疗晚期肿瘤小鼠可改善体外T细胞功能和生长。(C) 2009 Elsevier B.V.版权所有
Myeloid derived suppressor cells (MDSCs) accumulate in 4T1 mammary carcinoma bearing mice and present a barrier to the success of adoptive immunotherapy (AIT) by suppressing T cell immunity. in this study, we investigated the inhibition of MDSCs by gemcitabine (GEM). a chemotherapy agent that may have favorable immunologic effects. BALB/c mice were inoculated with 4T1 mammary carcinoma cells and treated with GEM either once a week starting 5 days after tumor inoculation (EARLY GEM) or as a single dose at days 2025 (LATE GEM). Splenic mononuclear cells were isolated, activated in vitro, expanded, and stimulated with tumor antigen. T cells were then used for AIT to treat tumor-bearing mice. EARLY GEM treatment of 4T1 tumor-bearing mice significantly inhibited tumor growth, reduced splenomegaly, and significantly decreased MDSC proportion in the spleen. Support for a direct effect was demonstrated through suppression of MDSCs in spleens, bone marrow, and blood harvested 24 and 48 In after LATE GEM treatment, despite no significant decrease in tumor burden. Interestingly, treatment of tumor-bearing mice with GEM augmented in vitro expansion of splenic T cells and boosted IFN-gamma secretion in response to stimulation by tumor antigen. However, despite GEM-mediated inhibition of MDSC suppression, splenic T cells from mice with advanced tumors were ineffective in vivo against established tumors. This study provides support for direct inhibition of MDSCs and direct reduction of tumor burden by GEM in 4T1 tumor-bearing mice. GEM treatment of mice with advanced tumors improves T cell function and growth in vitro. (C) 2009 Elsevier B.V. All rights reserved.