调节免疫系统作用提高癌症化疗效果
2019-11-26 抗癌健康网
专注健康 关爱生命一项发表在Nature Medicine杂志上的研究中，研究人员提出两种经常用于治疗消化道癌和乳腺癌的化疗药物可能促进肿瘤的发展，其机制是通过调节机体的抗肿瘤免疫反应。这些研究结果揭示了免疫系统如何限制某些癌症化疗药物的有效性。
化疗是消除癌细胞最常用的治疗方法之一。这些药物杀死所有细胞或阻止其扩散。除了其直接的毒性作用，化疗药物似乎也对免疫系统有作用，可能调节机体直接的抗肿瘤免疫反应。
在新研究中，研究人员观察到化疗药物5-氟二氧嘧啶和吉西他滨（常用于治疗结肠癌，乳腺癌和胰腺癌症）激活蛋白质复合体NLRP3。此活化会导致免疫细胞释放促炎性细胞因子（白介素IL-1β。这种细胞因子 “扭曲”淋巴T细胞的免疫应答，并导致产生另一种细胞因子（细胞因子IL-17），IL-17有促肿瘤血管生成的属性。
研究结果使人们有可能确定炎性激活限制化疗效果的机制。现在面临的挑战是，我们是否可以防止免疫反应的激活。就此，研究人员实验了两种不同的策略。
首先测试两种抗癌药物对炎性体NLRP3或细胞因子IL-17缺陷小鼠的作用。在这些情况下，研究人员发现化疗药物的抗肿瘤活性实际上增加了，表明这两种元素（NLRP3和IL-17）实际上是抑制了化疗药物作用。
第二个策略是使用IL-1β抑制剂治疗小鼠。在这里，化疗药物抗癌作用再次增加。这些结果表明，针对炎性体和IL-1β，联合两个化疗药物可以改善增强化疗药物的有效性。（生物谷：Bioon.com）
doi:10.1038/nm.2999
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Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth.
Mélanie Bruchard, Grégoire Mignot, et al.
Chemotherapeutic agents are widely used for cancer treatment. In addition to their direct cytotoxic effects, these agents harness the host's immune system, which contributes to their antitumor activity. Here we show that two clinically used chemotherapeutic agents, gemcitabine (Gem) and 5-fluorouracil (5FU), activate the NOD-like receptor family, pyrin domain containing-3 protein (Nlrp3)-dependent caspase-1 activation complex (termed the inflammasome) in myeloid-derived suppressor cells (MDSCs), leading to production of interleukin-1β (IL-1β), which curtails anticancer immunity. Chemotherapy-triggered IL-1β secretion relied on lysosomal permeabilization and the release of cathepsin B, which bound to Nlrp3 and drove caspase-1 activation. MDSC-derived IL-1β induced secretion of IL-17 by CD4+ T cells, which blunted the anticancer efficacy of the chemotherapy. Accordingly, Gem and 5FU exerted higher antitumor effects when tumors were established in Nlrp3?/? or Casp1?/? mice or wild-type mice treated with interleukin-1 receptor antagonist (IL-1Ra). Altogether, these results identify how activation of the Nlrp3 inflammasome in MDSCs by 5FU and Gem limits the antitumor efficacy of these chemotherapeutic agents.
