Lighting a Fire: Can We Harness Pyroptosis to Ignite Antitumor Immunity?
Lighting a Fire: Can We Harness Pyroptosis to Ignite Antitumor Immunity?
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DOI：
10.1158/2326-6066.cir-20-0525
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发表时间：
2021-01
影响因子：
10.1
通讯作者：
Lieberman J
中科院分区：
文献类型：
--
作者：
Zhang Z;Zhang Y;Lieberman J
目前癌症免疫疗法在一些患者中取得了令人印象深刻的成功，但在大多数患者中缺乏有效性，这表明需要额外的策略来促进抗肿瘤免疫。癌细胞如何死亡，无论是自发的还是对治疗干预的反应，对动员的免疫反应类型有着深远的影响。在这里，我们回顾研究，突出了以前未被重视的作用gasdermin介导的炎症性死亡（pyroptosis），以促进抗肿瘤免疫，并确定gasdermin E作为一种肿瘤抑制剂。自然杀伤细胞和细胞毒性T淋巴细胞对肿瘤细胞的免疫消除是抗肿瘤免疫的最后关键事件，以前认为是非炎症性的。研究表明，当细胞死亡诱导颗粒酶直接切割并激活gasdermin时，肿瘤细胞中gasdermin的表达将免疫细胞介导的杀伤转化为炎性细胞凋亡。颗粒酶B切割gasdermin E，颗粒酶A切割gasdermin B。这些数据表明，有可能利用肿瘤中的焦亡来引发对免疫冷肿瘤的有效免疫反应。Gasdermin表达还增加癌症治疗的毒性-B细胞白血病和淋巴瘤的Gasdermin E表达是CAR T细胞细胞因子风暴的根本原因，并且其在正常组织中的表达促进化疗药物的毒性。尽管我们对细胞凋亡在癌症中的作用的认识在不断增长，但仍有很多东西需要了解-什么激活了它，它是如何调节的，何时有益，以及如何在治疗上利用它来改善癌症免疫治疗或减少治疗相关的毒性。
The impressive success of current cancer immunotherapy in some patients, but lack of effectiveness in most patients, suggests that additional strategies to promote anti-tumor immunity are needed. How cancer cells die, whether spontaneously or in response to therapeutic intervention, has a profound effect on the type of immune response mobilized. Here, we review research that highlights a previously unappreciated role of gasdermin-mediated inflammatory death (pyroptosis) to promote anti-tumor immunity and identifies gasdermin E as a tumor suppressor. Immune elimination of tumor cells by natural killer cells and cytotoxic T lymphocytes, which is the final key event in anti-tumor immunity, was previously thought to be noninflammatory. The research shows that gasdermin expression in tumor cells converts immune cell–mediated killing to inflammatory pyroptosis when cell death–inducing granzymes directly cleave and activate gasdermins. Granzyme B cleaves gasdermin E and granzyme A cleaves gasdermin B. The data suggest the potential to harness pyroptosis in the tumor to ignite an effective immune response to immunologically cold tumors. Gasdermin expression also augments toxicity of cancer therapy—gasdermin E expression by B cell leukemias and lymphomas is a root cause of CAR T–cell cytokine storm and its expression in normal tissues promotes the toxicity of chemotherapeutic drugs. Even though our knowledge about the role of pyroptosis in cancer is growing, there is still a lot to learn—what activates it, how it is regulated, when it is beneficial, and how it can be harnessed therapeutically to improve cancer immunotherapy or reduce therapy-related toxicity.