Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA.
Graduate Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
Nat Commun. 2020 Dec 7;11(1):6299. doi: 10.1038/s41467-020-19970-9.
Induction of tumor cell death is the therapeutic goal for most anticancer drugs. Yet, a mode of drug-induced cell death, known as immunogenic cell death (ICD), can propagate antitumoral immunity to augment therapeutic efficacy. Currently, the molecular hallmark of ICD features the release of damage-associated molecular patterns (DAMPs) by dying cancer cells. Here, we show that gemcitabine, a standard chemotherapy for various solid tumors, triggers hallmark immunostimualtory DAMP release (e.g., calreticulin, HSP70, and HMGB1); however, is unable to induce ICD. Mechanistic studies reveal gemcitabine concurrently triggers prostaglandin E release as an inhibitory DAMP to counterpoise the adjuvanticity of immunostimulatory DAMPs. Pharmacological blockade of prostaglandin E biosythesis favors CD103 dendritic cell activation that primes a Tc1-polarized CD8 T cell response to bolster tumor rejection. Herein, we postulate that an intricate balance between immunostimulatory and inhibitory DAMPs could determine the outcome of drug-induced ICD and pose COX-2/prostaglandin E blockade as a strategy to harness ICD.
诱导肿瘤细胞死亡是大多数抗癌药物的治疗目标。然而，一种称为免疫原性细胞死亡（ICD）的药物诱导细胞死亡模式可以增强抗肿瘤免疫，从而提高治疗效果。目前，ICD 的分子标志特征是垂死癌细胞释放损伤相关分子模式（DAMPs）。在这里，我们表明，吉西他滨是各种实体瘤的标准化疗药物，可引发标志性免疫刺激 DAMP 释放（例如钙网蛋白、HSP70 和 HMGB1）；然而，它不能诱导 ICD。机制研究表明，吉西他滨同时触发前列腺素 E 释放作为抑制性 DAMPs，以抵消免疫刺激性 DAMPs 的佐剂作用。前列腺素 E 生物合成的药理学阻断有利于 CD103 树突状细胞的激活，从而启动 Tc1 极化的 CD8 T 细胞反应，以增强肿瘤排斥。在此，我们假设免疫刺激性和抑制性 DAMPs 之间的复杂平衡可能决定药物诱导的 ICD 的结果，并提出 COX-2/前列腺素 E 阻断作为利用 ICD 的策略。
