Program in Cellular and Molecular Medicine, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
Cancer Immunol Res. 2021 Jan;9(1):2-7. doi: 10.1158/2326-6066.CIR-20-0525.
The impressive success of current cancer immunotherapy in some patients but lack of effectiveness in most patients suggests that additional strategies to promote antitumor 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 antitumor 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 antitumor 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 chimeric antigen receptor (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.
当前癌症免疫疗法在一些患者中取得了令人瞩目的成功，但在大多数患者中效果不佳，这表明需要额外的策略来促进抗肿瘤免疫。癌细胞的死亡方式，无论是自发的还是对治疗干预的反应，都会对动员的免疫反应类型产生深远的影响。在这里，我们回顾了强调gasdermin 介导的炎症性死亡（细胞焦亡）促进抗肿瘤免疫的作用以及鉴定 gasdermin E 作为肿瘤抑制因子的研究。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终关键事件，以前被认为是非炎症性的。研究表明，当细胞死亡诱导颗粒酶直接切割和激活 gasdermins 时，肿瘤细胞中 gasdermin 的表达将免疫细胞介导的杀伤转化为炎症性细胞焦亡。颗粒酶 B 切割 gasdermin E，而颗粒酶 A 切割 gasdermin B。这些数据表明，有可能利用肿瘤中的细胞焦亡来引发对免疫冷肿瘤的有效免疫反应。Gasdermin 的表达还增强了癌症治疗的毒性-表达在 B 细胞白血病和淋巴瘤中的 gasdermin E 是嵌合抗原受体（CAR）T 细胞细胞因子风暴的根本原因，其在正常组织中的表达促进了化疗药物的毒性。尽管我们对细胞焦亡在癌症中的作用的了解正在增加，但仍有很多需要了解-是什么激活了它，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疗法或降低治疗相关毒性。
