Nature免疫疗法突破:剑桥大学科学家让T细胞“活更久”
2016/10/28
本月,免疫疗法中的PD-1/PD-L1抗体“家族”收获多个喜讯。首个治疗转移性非小细胞肺癌(NSCLC)的PD-L1抗体(Atezolizumab)获批,PD-1抗体Keytruda正式被批准用于NSCLC一线治疗,这些消息再次证明了癌症免疫疗法的绝对实力。当然,近几年,免疫疗法的进步远不止这些,包括过继细胞疗法、联合治疗在内的技术也在飞速发展中。近日,Nature及Nature Medicine杂志上相继发表了两项突破成果,为癌症治疗带来了新的可能。

10月26日,Nature杂志在线发表了题为“S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate”的论文。来自剑桥大学、新加坡国立大学、加州大学圣地亚哥分校等机构的科学家们发现,一个小分子能够将短暂存活的“杀伤性T细胞(killer T-cells)”转变为可再生的细胞。这些细胞能够在体内存在更长的时间,并且在需要摧毁肿瘤细胞时激活。

为了保护我们免受病毒和细菌的入侵,以及内部威胁(如恶性肿瘤细胞),我们的免疫系统“雇佣”了一大群免疫细胞。就像军队由不同类型的士兵组成一样,每一类免疫细胞也具有特定的功能。其中,杀伤性T细胞的主要功能是在体内“巡逻”,识别和摧毁被感染的细胞和癌细胞。

目前,科学家们正在尝试利用这类细胞对抗癌症。具体方法是对T细胞进行改造,使其能够识别癌细胞,在体外将其大量扩增后,再回输到患者体内。这一技术被称为过继T细胞疗法。然而,由于杀伤性T细胞存活时间短(大部分细胞在回输后3天内会消失),因此,在彻底消灭肿瘤前,这支“军队”可能就先阵亡了。

此次,发表Nature上的这项新研究有望帮助科学家们克服这一阻碍免疫疗法发展的关键障碍之一。研究人员鉴定出了小分子2-hydroxyglutarate(2-HG,之前被知晓的作用是触发肿瘤细胞的异常生长)的一种新作用。这一分子一种略有不同的形式在T细胞功能中扮演了关键的角色:它能够使T细胞保持在记忆状态(memory state)。在这种状态下,细胞能够自我更新,长时间存在,且能够重新激活,对抗感染或癌症。

研究人员发现,通过增加T细胞中的2-HG水平,能够产生更加有效对抗肿瘤的细胞。该研究的通讯作者Randall Johnson教授说:“从某种意义上说,我们创建了一群可再生的细胞,能够在长时间内待命,在必要时启动攻击。这一方法有望为患者提供更加长久的免疫力,从而让免疫疗法更加有效。”

多管齐下,消灭肿瘤

除了免疫细胞疗法的新进展外,本周发表在Nature Medicine上的一项研究中(题目:Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses),MIT的科学家们找对了对抗癌症的免疫疗法新型“组合拳”。

肿瘤细胞通常会分泌化合物来抑制免疫系统,保护自己免受攻击。为了克服这一点,科学家试图找到“唤醒”免疫系统的方法,其中包括了先天免疫系统和适应性免疫系统。这项新研究正是同时利用了这两支系统。

科学家们使用的组合疗法具体包括以下4部分:一个靶向肿瘤的抗体、一种T细胞疫苗、半衰期延长的重组白介素-2(interleukin-2,IL-2)以及一个阻断T细胞上PD-1受体的分子。每一个分子在增强整体免疫反应中都起着至关重要的作用:抗体刺激额外免疫细胞(帮助激活T细胞)的招募;疫苗刺激T细胞的增殖;IL-2帮助T细胞群体迅速扩大;抗PD-1分子帮助延长T细胞活跃时间。

研究人员在3种不同类型的肿瘤小鼠模型中检测了这一联合疗法,包括黑色素瘤、淋巴瘤和乳腺癌。结果发现,这些小鼠中,约75%的肿瘤被完全清除。此外,6个月后,研究人员再注射肿瘤细胞到相同的小鼠中,发现它们的免疫系统能够完全清除肿瘤细胞。

科学家们表示,利用这一联合疗法作为模板,研究人员可以替换其它类型的抗体和疫苗,靶向不同类型的肿瘤。

参考资料:

University of Cambridge:Self-renewable killer cells could be key to making cancer immunotherapy work

MIT:Fighting cancer with the power of immunity

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  • S-2-hydroxyglutarate regulates CD8+ T-lymphocyte fate

    R-2-hydroxyglutarate accumulates to millimolar levels in cancers with gain-of-function isocitrate dehydrogenase 1/2 mutations. These levels of R-2-hydroxyglutarate affect 2-oxoglutarate-dependent dioxygenases. Both R- and S-2-hydroxyglutarate, the other enantiomer of this metabolite, are detectible in healthy individuals, yet their physiological function remains elusive. Here we show that CD8+ T-lymphocytes accumulate 2-hydroxyglutarate in response to T-cell receptor triggering. This increases to millimolar levels in physiological oxygen conditions, via a hypoxia inducible factor 1 alpha-dependent mechanism. S-2-hydroxyglutarate predominates over R-2-hydroxyglutarate in activated T cells, and we demonstrate alterations in markers of CD8+ T-lymphocyte differentiation in response to this metabolite. Modulation of histone and DNA demethylation as well as hypoxia inducible factor 1 alpha stability mediate these effects. S-2-hydroxyglutarate treatment greatly enhances the in vivo proliferation, persistence and anti-tumour capacity of adoptively transferred CD8+ T-lymphocytes. Thus S-2-hydroxyglutarate acts as an immunometabolite that links environmental context, via a metabolic-epigenetic axis, to immune fate and function.

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  • Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses

    Checkpoint blockade with antibodies specific for cytotoxic T lymphocyte–associated protein (CTLA)-4 or programmed cell death 1 (PDCD1; also known as PD-1) elicits durable tumor regression in metastatic cancer, but these dramatic responses are confined to a minority of patients. This suboptimal outcome is probably due in part to the complex network of immunosuppressive pathways present in advanced tumors, which are unlikely to be overcome by intervention at a single signaling checkpoint. Here we describe a combination immunotherapy that recruits a variety of innate and adaptive immune cells to eliminate large tumor burdens in syngeneic tumor models and a genetically engineered mouse model of melanoma; to our knowledge tumors of this size have not previously been curable by treatments relying on endogenous immunity. Maximal antitumor efficacy required four components: a tumor-antigen-targeting antibody, a recombinant interleukin-2 with an extended half-life, anti-PD-1 and a powerful T cell vaccine. Depletion experiments revealed that CD8+ T cells, cross-presenting dendritic cells and several other innate immune cell subsets were required for tumor regression. Effective treatment induced infiltration of immune cells and production of inflammatory cytokines in the tumor, enhanced antibody-mediated tumor antigen uptake and promoted antigen spreading. These results demonstrate the capacity of an elicited endogenous immune response to destroy large, established tumors and elucidate essential characteristics of combination immunotherapies that are capable of curing a majority of tumors in experimental settings typically viewed as intractable.

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