肿瘤细胞治疗研究
英文原题：Systemic administration of liposomal trehalose dimycolate induces NK1.1⁺ cell mediated antitumor immunity in bladder cancer.
Systemic administration of liposomal trehalose dimycolate induces NK1.1⁺ cell mediated antitumor immunity in bladder cancer.
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膀胱内灌注卡介苗（BCG）是膀胱癌最有效的免疫疗法，但活BCG细菌可能引起严重不良事件，且仅限于局部给药。在此，我们报告了一种毒性较低的治疗方案，使用海藻糖6,6-二霉菌酸酯（TDM），一种主要的BCG细胞壁糖脂，可激活先天免疫并具有佐剂效应。
我们先前建立了含有TDM的亲水性阳离子脂质体（Lip-TDM），并发现局部给予Lip-TDM通过树突状细胞成熟诱导CD8+ T细胞激活，对皮下接种的肿瘤发挥抗肿瘤作用。
在此，我们进一步证明，腹腔内给予Lip-TDM在N-丁基-N-(4-羟丁基)亚硝胺诱导的原位膀胱癌小鼠模型中发挥抗肿瘤作用。Lip-TDM治疗组的膀胱癌发生率显著低于Lip-CON治疗组（60.8% [23例中14例] 对比 95.4% [22例中21例]，p < 0.01）。腹腔内给予Lip-TDM增强了树突状细胞和巨噬细胞的全身激活，增加了CD8+ T细胞的浸润。
此外，Lip-TDM治疗诱导了自然杀伤（NK）细胞对肿瘤的细胞毒性活性，同时在淋巴组织中富集调节性NK群体。这种抗肿瘤效应在野生型小鼠中观察到，但在NK细胞耗竭的小鼠中未观察到。这些结果强调NK1.1淋巴细胞是Lip-TDM诱导获得性免疫抗肿瘤反应所必需的。
我们的发现表明，Lip-TDM是一种非感染性、NK激活的抗肿瘤剂，可通过腹腔内或全身给药，作为BCG的潜在替代方案。
Intravesical Bacillus Calmette-Guerin (BCG) administration is the most effective immunotherapy for bladder cancer, but live BCG bacteria may cause serious adverse events and are limited to local administration.
Here, we report the formulation of a less toxic treatment using trehalose 6,6 -dimycolate (TDM), a predominant BCG cell wall glycolipid, that activates innate immunity and carries an adjuvant effect.
We previously established hydrophilic cationic liposomes incorporating TDM (Lip-TDM) and found that local administration of Lip-TDM exerts antitumor effects on subcutaneously inoculated tumors by inducing CD8+ T cell activation via dendritic cell maturation.
Here, we further demonstrate that intraperitoneal administration of Lip-TDM exerts antitumor effects in an N-butyl-N-(4-hydroxybutyl) nitrosamine-induced, orthotopic bladder carcinogenesis mouse model. The incidence of bladder cancer in the Lip-TDM treated group was significantly lower compared to the Lip-CON treated group (60. 8% [14 out of 23] versus 95. 4% [21 out of 22], p < 0. 01). Intraperitoneal administration of Lip-TDM enhanced the systemic activation of dendric cells and macrophages, increasing infiltration of CD8+ T cells.
Furthermore, Lip-TDM treatment induced both natural killer (NK) cell cytotoxic activity against tumors while enriching regulatory NK populations in lymphoid tissues. This antitumor effect was seen in WT mice but not NK cell-depleted mice. These results highlight NK1. 1 lymphocytes as essential for Lip-TDM to induce the acquired immune anti-tumor response.
Our findings suggest that Lip-TDM is a non-infectious, NK-activating, anti-tumor agent which can be administered intraperitoneally or systemically as a potential alternative to BCG.
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