Targeting TLR-4 with a novel pharmaceutical grade plant derived agonist, Immunomax®, as a therapeutic strategy for metastatic breast cancer.
Targeting TLR-4 with a novel pharmaceutical grade plant derived agonist, Immunomax®, as a therapeutic strategy for metastatic breast cancer.
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DOI：
10.1186/s12967-014-0322-y
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发表时间：
2014-11-29
影响因子：
7.4
通讯作者：
Ataullakhanov RI
中科院分区：
文献类型：
--
作者：
Ghochikyan A;Pichugin A;Bagaev A;Davtyan A;Hovakimyan A;Tukhvatulin A;Davtyan H;Shcheblyakov D;Logunov D;Chulkina M;Savilova A;Trofimov D;Nelson EL;Agadjanyan MG;Ataullakhanov RI
以前我们证明，原发性4 T1肿瘤的切除仅略微降低小鼠存活率，但重要的是，产生了一个“机会之窗”，抑制细胞减少，活化T细胞群增加。这表明，在此期间免疫刺激剂对免疫系统的额外激活可增强抗肿瘤免疫力，并可能在此严格模型中根除微转移性疾病。我们假设，免疫刺激剂Immunomax®（其由植物来源的多糖组成）在人类中是无毒的，并且在感染性疾病治疗期间刺激免疫防御，还可能具有抗肿瘤活性，并且当存在内源性抗肿瘤应答时以及在切除后转移性乳腺癌模型中的“机会窗口”期间在佐剂环境中是有益的。在这里，我们提供了Immunomax®在切除后的4 T1乳腺癌小鼠模型中显示出消除微转移疾病的能力的初步报告。通过分析小鼠肺匀浆中的存活率和自发性克隆形成肿瘤细胞的数量来评估Immunomax®的功效。使用流式细胞术评估活化的NK、CD 4+和CD 8+细胞以及髓源性抑制细胞和Treg细胞的频率。分选高度纯化的小鼠和人树突状细胞和NK细胞，并通过流式细胞术评估Immunomax®对这些细胞活化状态的影响。通过NF-κB/SEAP报告基因分析、WB、RT-PCR等方法，检测Immunomax®作为TLR-4激动剂的特性。Immunomax®注射显著延长了小鼠的总体生存期，治愈了31%的小鼠。这种免疫刺激剂通过TLR-4激活DC，这反过来又刺激杀肿瘤NK细胞，并在体外完全抑制4 T1细胞的生长。来自健康供体的PBMC与Immunomax®的孵育通过活化浆细胞样DC来活化NK细胞，导致与未处理的细胞相比在杀伤人NK靶细胞K562方面显著更高的功效。这是第一次证明Immunomax®是TLR-4激动剂，也是第一次报道这种药用级免疫刺激剂在增强抗肿瘤活性方面的作用，表明将Immunomax®纳入开发乳腺癌治疗策略可能是有益的，并且比检查点抑制剂具有更低的潜在毒性。本文的在线版本（doi：10.1186/s12967-014-0322-y）包含补充材料，可供授权用户使用。
Previously we demonstrated that the resection of primary 4T1 tumors only slightly prolongs mouse survival, but importantly, creates a “window of opportunity” with attenuated suppressor cell and increased activated T cell populations. This suggests that additional activation of the immune system by immunostimulatory agents during this period may enhance anti-tumor immunity and potentially eradicate micro-metastatic disease in this stringent model. We hypothesized that the immunostimulator Immunomax®, which is comprised of a plant-derived polysaccharide, is non-toxic in humans and stimulates immune defense during the infectious diseases treatment, may have also anti-tumor activity and be beneficial in the adjuvant setting when endogenous anti-tumor responses are present and during the “window of opportunity” in post-resection metastatic breast cancer model. Here we provide the initial report that Immunomax® demonstrates the capacity to eliminate micro-metastatic disease in the post-resection, 4T1 mouse model of breast cancer. The efficacy of Immunomax® was evaluated by analyzing survival rate and the number of spontaneous clonogenic tumor cells in the lung homogenates of mice. The frequencies of activated NK, CD4+ and CD8+ cells as well as myeloid-derived suppressor cells and Treg cells were evaluated using flow cytometry. Highly purified mouse and human dendritic and NK cells were sorted and the effect of Immunomax® on activation status of these cells was assessed by flow cytometry. The property of Immunomax® as TLR-4 agonist was determined by NF-κB/SEAP reporter gene assay, WB, RT-PCR. Immunomax® injections significantly prolonged overall survival and cured 31% of mice. This immunostimulator activates DCs via the TLR-4, which in turn stimulates tumoricidal NK cells and in vitro, completely inhibits growth of 4T1 cells. Incubation of PBMC from healthy donors with Immunomax® activates NK cells via activation of plasmacytoid DC leading significantly higher efficacy in killing of human NK-target cells K562 compared with non-treated cells. This is the first demonstration that Immunomax® is a TLR-4 agonist and the first report of a documented role for this pharmaceutical grade immunostimulator in augmenting anti-tumor activity, suggesting that incorporation of Immunomax® into developing breast cancer therapeutic strategies may be beneficial and with less potential toxicity than checkpoint inhibitors. The online version of this article (doi:10.1186/s12967-014-0322-y) contains supplementary material, which is available to authorized users.
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DOI：
10.1084/jem.20010938
发表时间：
2002-02-04
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gerosa F;Baldani-Guerra B;Nisii C;Marchesini V;Carra G;Trinchieri G
通讯作者：
Trinchieri G
影响因子：
4
作者：
Mai CW;Kang YB;Pichika MR
通讯作者：
Pichika MR
影响因子：
3.6
作者：
Matsunaga, Naoko;Tsuchimori, Noboru;Ii, Masayuki
通讯作者：
Ii, Masayuki
影响因子：
64.8
作者：
Mellman, Ira;Coukos, George;Dranoff, Glenn
通讯作者：
Dranoff, Glenn
影响因子：
3.7
作者：
Ahmed, Abubakr;Wang, Jiang Huai;Redmond, H. Paul
通讯作者：
Redmond, H. Paul