Synergistic activation of macrophages via CD40 and TLR9 results in T cell independent antitumor effects
Synergistic activation of macrophages via CD40 and TLR9 results in T cell independent antitumor effects
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DOI：
10.4049/jimmunol.176.1.309
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发表时间：
2006-01-01
影响因子：
4.4
通讯作者：
Rakhmilevich, AL
中科院分区：
文献类型：
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作者：
Buhtoiarov, IN;Lum, HD;Rakhmilevich, AL
我们之前已经证明巨噬细胞（M phi）可以通过CD40连接激活，在体外对肿瘤细胞具有细胞毒性。本研究表明，用激动性抗cd40单抗（anti-CD40）治疗小鼠可诱导M phi细胞内TLR9上调，并诱导它们对含CpG的寡脱氧核苷酸（CpG）做出反应，从而产生协同激活。抗cd40和CpG之间的协同作用通过mphi增加ifn - γ、IL-12、tnf - α和NO的产生，以及mphi增强对肿瘤细胞的凋亡作用得到证实。抗cd40 + CpG处理后细胞毒性M - phi的激活依赖于ifn - γ，而不依赖于TNF-a或NO，并且不需要T细胞和NK细胞。抗cd40和CpG在体内也协同抑制免疫正常和免疫缺陷小鼠的肿瘤生长。在SCID/beige小鼠中，二氧化硅处理的M phi失活消除了其抗肿瘤作用。综上所述，我们的研究结果表明，MO可以通过CD40/TLR9连接激活，在体外杀死肿瘤细胞，在体内甚至在免疫功能低下的荷瘤宿主中抑制肿瘤生长，这表明这种基于M - phi的免疫治疗策略可能适合临床试验。
We have previously shown that macrophages (M phi) can be activated by CD40 ligation to become cytotoxic against tumor cells in vitro. Here we show that treatment of mice with agonistic anti-CD40 mAb (anti-CD40) induced up-regulation of intracellular TLR9 in M phi and primed them to respond to CpG-containing oligodeoxynucleotides (CpG), resulting in synergistic activation. The synergy between anti-CD40 and CpG was evidenced by increased production of IFN-gamma, IL-12, TNF-alpha, and NO by M phi, as well as by augmented apoptogenic effects of M phi against tumor cells in vitro. The activation of cytotoxic M phi after anti-CD40 plus CpG treatment was dependent on IFN-gamma but not TNF-a or NO, and did not require T cells and NK cells. Anti-CD40 and CpG also synergized in vivo in retardation of tumor growth in both immunocompetent and immunodeficient mice. Inactivation of M phi in SCID/beige mice by silica treatment abrogated the antitumor effect. Taken together, our results show that MO can be activated via CD40/TLR9 ligation to kill tumor cells in vitro and inhibit tumor growth in vivo even in immunocompromised tumor-bearing hosts, indicating that this M phi-based immunotherapeutic strategy may be appropriate for clinical testing.