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Sci Transl Med:轮状病毒疫苗助力儿童肿瘤告别免疫抑制

2019-11-04 Ruthy 转化医学网

近日,法国的一个研究团队将轮状病毒疫苗应用于癌症治疗,不仅发挥了其溶瘤作用,还可消除“冷肿瘤”存在的免疫抑制环境,成功克服了ICB治疗的耐药性!

近日,法国的一个研究团队将轮状病毒疫苗应用于癌症治疗,不仅发挥了其溶瘤作用,还可消除“冷肿瘤”存在的免疫抑制环境,成功克服了ICB治疗的耐药性!

ICB——抗癌新希望,却对“冷肿瘤”无计可施

免疫检查点是一类免疫抑制性分子,正常情况下可通过调节免疫反应的强度和广度来避免正常组织的损伤和破坏,而肿瘤细胞则可通过激活免疫检查点活性逃避免疫系统的监视。为了将肿瘤细胞“绳之于法”,ICB应运而生。ICB可通过拮抗免疫检查点蛋白,促进T细胞活化,进而产生抗肿瘤免疫效应。简而言之,ICB就是为患者自身免疫细胞发挥识别和杀伤肿瘤的作用扫清一切障碍。

但是,肿瘤除了表达免疫检查点受体的配体来抑制T细胞激活以外,还可以在肿瘤周围形成免疫抑制的微环境。多项实验证明,肿瘤局部或血液循环中已经存在的免疫环境对ICB疗法的疗效起到重要作用,其中效应T细胞的活性是抗癌反应的核心。而多数肿瘤患者确诊时原发瘤中没有或只有很少浸润的T淋巴细胞,同时肿瘤组织还可募集不成熟的浆细胞样树突状细胞(pDC),活化具有免疫抑制能力的调节性T细胞(Treg)和髓样来源抑制性细胞(MDSC)的功能,从而使肿瘤处于免疫抑制状态,这就是“冷肿瘤”。这种肿瘤中ICB的结合受体被“霸占”,ICB及其驱动的战士T细胞皆被拒之门外,ICB自然无法发挥作用。所以,想让ICB发挥作用,首先就要给“冷肿瘤”“加热”,解除其免疫抑制性。

轮状病毒疫苗溶瘤、复免疫原性两不相误

说到恢复肿瘤免疫原性,目前研究较多的是利用溶瘤病毒来引发抗肿瘤免疫力。溶瘤病毒能够有选择性地感染并且在肿瘤细胞中复制,最终引起肿瘤细胞裂解。而且,溶瘤病毒的抗肿瘤免疫反应的持久性也值得期待,其与ICB的联合疗法是未来“冷肿瘤”治疗的重要发展方向。但是,这种组合疗法涉及对病毒毒性的控制、临床暴露风险和大面积推广法规不健全等问题,尤其是对儿童患者更是不容许轻易尝试。那么,是否有较为安全的做法呢?

轮状病毒疫苗和ICB发挥协同作用消灭肿瘤

活性病毒安全性不够,我们自然而然地会想起另一种选择——病毒疫苗。研究人员在大量实验后,确定了轮状病毒疫苗具有免疫刺激和溶瘤特性。他们发现,轮状病毒疫苗可克服肿瘤对ICB的耐药性,同时与ICB发挥协同作用。他们指出,轮状病毒疫苗可以不依赖Toll样受体(TLR)的方式激活NF-κB途径介导的炎症反应,使T细胞向肿瘤组织聚集。“战士”已经聚集,战争自然一触即发。

另一方面,瘤内注射轮状病毒疫苗后,多种免疫活化相关基因表达明显上调,其中重要的免疫清除分子CD163在注射轮状病毒疫苗48小时后的表达上调是“冷肿瘤”被“加热”的重要原因之一,而I型干扰素(IFN)途径的大面积激活更是产生了绝对而持久的肿瘤特异性免疫力。IFN信号能够增强肿瘤细胞的免疫原性,导致MHC I的上调以及CD8 T细胞激活水平的提升。也就是说,轮状病毒疫苗疫苗是“绕过”免疫检查点对T细胞的“蒙蔽”作用,直接把T细胞“打醒”了!既然T细胞的功能已经被激活了,“冷肿瘤”自然“热”起来了。这种抗肿瘤免疫保留了轮状病毒的溶瘤特性,而且克服了ICB的耐药性,在“热”起来的肿瘤中与ICB携手合作,自然功效显着。

这项研究提供了有利于轮状病毒疫苗克服ICB耐药性的临床前理论基础,也为ICB的联合治疗提供了新思路,尤其为儿童的肿瘤治疗指出了更为安全有效的途径。相信不远的将来,肿瘤患者能迎来更多治愈的新希望,我们共同期待!

原始出处:
Shekarian T1,2,3,4, Sivado E2,3,5, Jallas AC2,5, et al.Repurposing rotavirus vaccines for intratumoral immunotherapy can overcome resistance to immune checkpoint blockade.Sci Transl Med. 2019 Oct 23;11(515). pii: eaat5025. doi: 10.1126/scitranslmed.aat5025.

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    2020-01-08 bsmagic9140
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    轮状病毒感染是导致儿童重症腹泻及低收入国家儿童腹泻死亡的最常见原因。2006年1月,《新英格兰医学杂志》(N Engl J Med)发表了两篇具有里程碑意义的文章,报告了五价(RV5, RotaTeq) 与单价(RV1,Rotarix)轮状病毒疫苗的安全性与有效性,这两项分别纳入超过6万名婴儿的研究表明,轮状病毒疫苗接种可有效预防婴儿轮状病毒性胃肠炎,且无

NEJM:单价轮状病毒疫苗可增加肠套叠风险

  虽然以往的大型临床实验并未显示轮状病毒疫苗与肠套叠发生风险增加之间的关联,但近期国际上有报道称,接种单价疫苗接种可能导致肠套叠发生风险小幅增加。   因此,美国研究人员对其国内婴幼儿接种单价疫苗后发生肠套叠的情况进行了大规模调查。结果显示,婴儿接种单价轮状病毒疫苗后肠套叠的发生率增加。该结果发表于2014年1月14日NEJM杂志上。   该项前瞻性临床研究共观测了超过

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