Flt3 ligand antitumor activity in a murine breast cancer model: A comparison with granulocyte-macrophage colony-stimulating factor and a potential mechanism of action
Flt3 ligand antitumor activity in a murine breast cancer model: A comparison with granulocyte-macrophage colony-stimulating factor and a potential mechanism of action
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DOI：
10.1089/10430349950017130
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发表时间：
1999-09-01
影响因子：
4.2
通讯作者：
Cornetta, K
中科院分区：
文献类型：
--
作者：
Braun, SE;Chen, KY;Cornetta, K
我们已经证明Flk2/Flt3配体（Flt3L）转导的肿瘤疫苗诱导可转移的T细胞保护小鼠乳腺癌细胞系，但与强效效应GM-CSF的直接比较，对预先建立的肿瘤的活性以及在该乳腺癌模型中的抗肿瘤反应机制尚不清楚。我们将表达Flt3L （C3Lt-Flt3L）和GM-CSF （C3L5- gmcsf）的C3L5细胞皮下注射到胸壁，然后在4周后，用亲代C3L5细胞刺激无肿瘤小鼠的对侧胸部，比较疫苗接种与C3L5细胞的差异。与仅表达新霉素磷酸转移酶（C3L5- g1n）的C3L5细胞相比，C3L5- flt3l和C3L5- gmcsf的体内生长速率降低（各25%的肿瘤形成）。然而，当无肿瘤动物用亲代C3L5细胞攻击时，C3L5- flt3l疫苗预防肿瘤生长的效果显著优于C3L5- gmcsf疫苗（33%接种C3L5- flt3l的动物发生肿瘤，而C3L5- gmcsf疫苗接种的动物发生肿瘤的比例为77%）。证实了两种疫苗的过继性免疫转移；来自无肿瘤小鼠的脾T细胞保护未成熟小鼠免受亲代肿瘤的攻击。为了模拟最小的疾病，亲本C3L5细胞在两种浓度下，5 × 10(3)个细胞；在C3L5-G1N或C3L5-Flt3L治疗前4天，将1 × 10(3)个细胞注射到对侧胸壁。C3L5-Flt3L治疗可减少对侧亲代肿瘤形成，67%肿瘤无发生；低，90%无肿瘤)，与C3L5-G1N治疗相比，低，0%无肿瘤)。抗asialo- gm(1)激活的自然杀伤细胞免疫耗竭阻断C3L5- flt31l -和C3L5 +可溶性flt3l介导的抗肿瘤活性。因此，flt3l转导的肿瘤细胞表现出强大的抗肿瘤活性，显然至少部分是由自然杀伤细胞介导的。
We have shown that Flk2/Flt3 ligand (Flt3L)-transduced tumor vaccine induces transferable T cell protection against a murine breast cancer cell line, but a direct comparison with the potent effector GM-CSF, the activity against preestablished tumors, and the mechanism of antitumor response in this breast cancer model are not known. We compared vaccination with C3L5 cells expressing Flt3L (C3Lt-Flt3L) and GM-CSF (C3L5-GMCSF) by injecting 1 x 10(4) cells subcutaneously into the chest wall and then, after 4 weeks, challenging the contralateral chest of tumor-free mice with parental C3L5 cells. C3L5-Flt3L and C3L5-GMCSF had reduced in vivo growth rates (25% tumor formation each) compared with 100% tumor formation of C3L5 cells expressing only neomycin phosphotransferase (C3L5-G1N). However, when tumor-free animals were challenged with parental C3L5 cells, C3L5-Flt3L vaccination was significantly better at preventing tumor growth (p < 0.05) than C3L5-GMCSF vaccination (33% of C3L5-Flt3L-vaccinated animals developed tumor compared with 77% of C3L5-GMCSF-vaccinated animals). Adoptive transfer of immunity for both vaccines was demonstrated; splenic T cells from tumor-free mice protected naive mice from parental tumor challenge. To simulate minimal disease, parental C3L5 cells at two concentrations thigh, 5 x 10(3) cells; or low, 1 x 10(3) cells) were injected into the contralateral chest wall 4 days prior to treatment with C3L5-G1N or C3L5-Flt3L. C3L5-Flt3L treatment decreased contralateral parental tumor formation thigh, 67% tumor free; low, 90% tumor free) compared with C3L5-G1N treatment thigh and low, 0% tumor free). Immunodepletion of activated natural killer cells with anti-asialo-GM(1) blocked C3L5-Flt31L- and C3L5 plus soluble Flt3L-mediated antitumor activity. Thus, Flt3L-transduced tumor cells manifest potent antitumor activity, apparently mediated, at least partially, by natural killer cells.