Nature新发现:调控“杀手T细胞”的关键蛋白
2017/12/13
近些年,免疫疗法已经成为癌症治疗的中坚力量,取得一系列佳绩。12月6日,《Nature》期刊在线发表一篇文章,揭示了一种关键蛋白——Runx3,负责调控杀手T细胞,促使其在肿瘤组织中聚集,增强抗癌特性。科学家们认为,靶向这一关键蛋白可以提高T细胞过继治疗癌症、感染的效果。


CD8+ T细胞,又称杀手T细胞(细胞毒性T细胞),是免疫系统中对抗外源入侵的关键细胞,会在机体内“巡逻”,识别和摧毁被感染的细胞和癌细胞。但是,这类细胞是如何离开淋巴系统,转移至皮肤、肠道、实体瘤等部位发挥特定作用的呢?

近期,来自于Scripps研究所、加州大学圣地亚哥分校的研究团队发现了操控这一过程的关键蛋白——Runx3,负责编程杀手T细胞,促使其转移至肿瘤、感染部位。

ACT方法的难题

目前,癌症免疫疗法中“启动”杀手T细胞有两个主要的策略:其一、通过免疫检查点抑制剂“解封”T细胞,促使它们更多地在肿瘤中累积;其二、过继性细胞转移(ACT)方法,即重新改造T细胞,再将其回输至患者体内识别、破坏特定肿瘤组织。

其中,ACT方法已在一些血液类癌症中展现出积极的治疗效果,但是在实体瘤上却不如人意。这里面关键的难题之一是调控T细胞转移至肿瘤组织的机制并不清晰。


Adam Getzler、Dapeng Wang和Matthew Pipkin(图片来源:The Scripps Research Institute)

找到转录因子Runx3

为了找到调控T细胞转移至淋巴系统之外的关键因子,Scripps研究所的免疫学和微生物学系副教授 Matthew Pipkin带领团队与圣地亚哥分校的Ananda Goldrath实验室合作,通过比较非淋巴组织、淋巴组织中的CD8+ T细胞的基因表达差异,获得一系列可能的基因列表,随后采用一种RNA干扰筛选策略,同时检测数千个基因的实际功能。

最终,他们找到了转录因子Runx3——调控非淋巴组织中T细胞的必要蛋白。具体而言,Runx3在杀手T细胞的染色体上行使功能,负责调控组织原位记忆CD8+T细胞的分化和稳态。

将成为新的切入点

研究团队以黑色素瘤小鼠为模型,进一步验证Runx3是否直接控制T细胞。结果显示,ACT获得的肿瘤特异性杀手T细胞会过度表达Runx3基因,减缓肿瘤生长、延长患者生存期。而且,缺乏Runx3的小鼠,其癌症病情发展比正常情况严重得多。

这意味着,Runx3活性会影响T细胞驻留在实体瘤中的能力。“我们可以通过上调Runx3活性,增强免疫细胞的抗癌效果,从而增加患者的生存几率。这将成为癌症免疫治疗新的切入点。” Matthew Pipkin教授解释道,“未来,靶向Runx3蛋白重编程免疫系统,并与过继性细胞治疗结合,从而促使它们以更高的效率攻击实体瘤。”

参考资料:

Scientists discover possible master switch for programming cancer immunotherapy

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  • Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours

    Tissue-resident memory CD8+ T (TRM) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses1,2. However, the molecular signals that control TRM cell differentiation and homeostasis are not fully understood. Here we show that mouse TRM precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of TRM cell differentiation and homeostasis. Runx3 was required to establish TRM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with TRM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8+ T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of TRM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.

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