COX-2 upregulation by tumour cells post-chemotherapy fuels the immune evasive dark side of cancer inflammation.

IF 4.1 Q2 CELL BIOLOGY Cell Stress Pub Date : 2022-08-16 eCollection Date: 2022-09-01 DOI:10.15698/cst2022.09.271
Charlotte R Bell, Santiago Zelenay
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Abstract

Cytotoxic therapies, such as chemotherapy and radiotherapy, are mainstays of cancer treatment for both early and unresectable, advanced disease. In addition to debulking the tumour mass through direct killing of proliferating tumour cells, these treatments can promote tumour control via immune-stimulating effects. Nonetheless, chemoresistance and tumour relapse remain huge clinical problems, suggesting that induction of anti-cancer immunity post-cytotoxic therapy is often weak, not durable and/or overcome by immune evasive mechanisms. In our recent study (Nat Commun 13:2063), we demonstrate that cancer cell-intrinsic activation of the cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) pathway post-chemotherapy treatment is a prevalent phenomenon which profoundly alters the inflammatory properties of the treated cancer cells. Of particular translational relevance, our findings support a model whereby upregulation of COX-2 expression and activity post-chemotherapy impairs the efficacy of the combination of PD-1 blockade and chemotherapy. Accordingly, pharmacological inhibition of COX-2 with celecoxib, an anti-inflammatory drug already used clinically, unleashed tumour control in preclinical models when given alongside chemoimmunotherapy combinations.

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化疗后肿瘤细胞对 COX-2 的上调助长了癌症炎症中免疫逃避的阴暗面。
化疗和放疗等细胞毒疗法是治疗早期和无法切除的晚期癌症的主要手段。除了通过直接杀死增殖的肿瘤细胞来清除肿瘤块外,这些疗法还能通过免疫刺激作用促进肿瘤控制。然而,化疗耐药性和肿瘤复发仍然是巨大的临床问题,这表明细胞毒疗法后诱导的抗癌免疫力往往较弱、不持久和/或被免疫逃避机制所克服。在我们最近的研究(Nat Commun 13:2063)中,我们证明了化疗后癌细胞内在激活环氧化酶(COX)-2/前列腺素 E2(PGE2)通路是一种普遍现象,它深刻改变了接受治疗的癌细胞的炎症特性。我们的研究结果支持这样一种模式,即化疗后 COX-2 表达和活性的上调会损害 PD-1 阻断和化疗联合疗法的疗效,这一点尤其具有转化意义。因此,用塞来昔布(一种已在临床上使用的抗炎药物)对 COX-2 进行药理抑制,在临床前模型中与化疗免疫疗法联合使用时,能有效控制肿瘤。
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来源期刊
Cell Stress
Cell Stress Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (miscellaneous)
CiteScore
13.50
自引率
0.00%
发文量
21
审稿时长
15 weeks
期刊介绍: Cell Stress is an open-access, peer-reviewed journal that is dedicated to publishing highly relevant research in the field of cellular pathology. The journal focuses on advancing our understanding of the molecular, mechanistic, phenotypic, and other critical aspects that underpin cellular dysfunction and disease. It specifically aims to foster cell biology research that is applicable to a range of significant human diseases, including neurodegenerative disorders, myopathies, mitochondriopathies, infectious diseases, cancer, and pathological aging. The scope of Cell Stress is broad, welcoming submissions that represent a spectrum of research from fundamental to translational and clinical studies. The journal is a valuable resource for scientists, educators, and policymakers worldwide, as well as for any individual with an interest in cellular pathology. It serves as a platform for the dissemination of research findings that are instrumental in the investigation, classification, diagnosis, and therapeutic management of major diseases. By being open-access, Cell Stress ensures that its content is freely available to a global audience, thereby promoting international scientific collaboration and accelerating the exchange of knowledge within the research community.
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