Inhibitory DAMPs in immunogenic cell death and its clinical implications.
Inhibitory DAMPs in immunogenic cell death and its clinical implications.
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DOI：
10.15698/cst2021.04.247
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发表时间：
2021-03-22
期刊：
影响因子：
6.4
通讯作者：
Chan KS
中科院分区：
文献类型：
--
作者：
Hayashi K;Nikolos F;Chan KS
人们越来越认识到垂死（或死亡）的细胞在其驻留组织内施加显着的生物学影响——通过细胞死亡期间表达或分泌的蛋白质和代谢物发挥旁分泌作用。例如，某些分子充当有效的有丝分裂原，促进邻近上皮细胞的重新增殖。其他无数的因子——被归类为损伤相关分子模式（DAMP）——充当“找到我”（引诱剂）、“吃我”（吞噬）或“危险”（激活）信号，用于招募和激活效应免疫细胞（例如树突状细胞）以引发炎症。自从发现免疫原性细胞死亡 (ICD) 以来，当前的教条将 DAMP 视为先天免疫细胞动员和激活的免疫佐剂，最终导致 CD8+ T 细胞的抗肿瘤交叉启动。然而，目前未知的是如何抵消这些免疫刺激性 DAMP 以避免免疫过度激活。我们最近的工作建立在这些基础之上，并引入前列腺素 E2 (PGE2) 作为一种“抑制性”DAMP——ICD 方程的一个新变量。前列腺素 E2 充当佐剂 DAMP 的免疫抑制平衡剂；因此，机械地排除 ICD。此外，长期争论的吉西他滨化疗的免疫原性取决于抑制性 DAMP 阻断，而不是像之前报道的那样由于其无法促进 DAMP 表达（即钙网蛋白）。这些发现很有趣。首先，尽管存在吉西他滨诱导的标志性 DAMP，但抑制性 DAMP（即 PGE2）足以阻碍 ICD 诱导的抗肿瘤免疫反应（图 1a）。其次，与传统方法那样在药理学上证实免疫刺激性 DAMP 不同，抑制性 DAMP 的缓解（使免疫刺激性和抑制性 DAMP 平衡向免疫刺激性 DAMP 倾斜）足以使细胞死亡具有免疫原性，并将吉西他滨转化为 ICD 诱导疗法（图 1b）。在这篇微观综述中，我们推断了我们的发现，并暗示了抑制性 DAMP 在药物发现中的价值、其在临床预后中的用途以及作为治疗干预的目标。
Dying (or dead) cells are increasingly recognized to impose significant biological influence within their tissues of residence—exerting paracrine effects through proteins and metabolites that are expressed or secreted during cellular demise. For example, certain molecules function as potent mitogens, promoting the repopulation of neighboring epithelial cells. And other myriad of factors—classified as damage-associated molecular patterns (DAMPs)—function as “find me” (attractant), “eat me” (engulfment), or “danger” (activation) signals for recruiting and activating effector immune cells (e.g., dendritic cells) to initiate inflammation. Since the discovery of immunogenic cell death (ICD), the current dogma posits DAMPs as immunological adjuvants for innate immune cell mobilization and activation, which ultimately leads to the antitumoral cross-priming of CD8+ T cells. However, what is currently unknown is how these immunostimulatory DAMPs are counteracted to avoid immune-overactivation. Our recent work builds on these fundamentals and introduces prostaglandin E2 (PGE2) as an ‘inhibitory' DAMP—a new variable to the ICD equation. Prostaglandin E2 functions as an immunosuppressive counterpoise of adjuvant DAMPs; and thus, mechanistically precludes ICD. Furthermore, the long-debated immunogenicity of gemcitabine chemotherapy was revealed to be contingent on inhibitory DAMP blockade and not due to its inability to promote DAMP expression (i.e., calreticulin) as previously reported. These findings were intriguing. First, despite the presence of gemcitabine-induced hallmark DAMPs, the inhibitory DAMP (i.e., PGE2) was sufficient to hinder the ICD-induced antitumoral immune response (Fig. 1a). And second, rather than pharmacologically substantiating immunostimulatory DAMPs as conventionally approached, the mitigation of the inhibitory DAMP—tipping the immunostimulatory and inhibitory DAMP balance in favor of immunostimulatory DAMPs—was sufficient to render the cell death immunogenic and converted gemcitabine into an ICD-inducing therapy (Fig. 1b). In this microreview, we extrapolate our findings and implicate the value of inhibitory DAMP(s) in drug discovery, its use for clinical prognosis, and as target(s) for therapeutic intervention.