Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations
AuthorsBell, Charlotte R
Pelly, Victoria S
Bromley, Christian. P
Earnshaw, Charles H
Koufaki, Maria A
AffiliationCancer Inflammation and Immunity Group, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK. Molecular Biology Core Facility, Cancer Research UK Manchester Institute, The University of Manchester, Alderley Park, Manchester, UK.
MetadataShow full item record
AbstractCytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production in cancer cells with pre-existing COX-2 activity. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Our findings suggest COX-2/PGE2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations.
CitationBell CR, Pelly VS, Moeini A, Chiang SC, Flanagan E, Bromley CP, et al. Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations. Vol. 13, Nature Communications. Springer Science and Business Media LLC; 2022.
- Multiple drug resistance-associated protein (MRP4) exports prostaglandin E2 (PGE2) and contributes to metastasis in basal/triple negative breast cancer.
- Authors: Kochel TJ, Reader JC, Ma X, Kundu N, Fulton AM
- Issue date: 2017 Jan 24
- Cyclooxygenase-2-prostaglandin E2-eicosanoid receptor inflammatory axis: a key player in Kaposi's sarcoma-associated herpes virus associated malignancies.
- Authors: Paul AG, Chandran B, Sharma-Walia N
- Issue date: 2013 Aug
- Upregulation of the S1P<sub>3</sub> receptor in metastatic breast cancer cells increases migration and invasion by induction of PGE<sub>2</sub> and EP<sub>2</sub>/EP<sub>4</sub> activation.
- Authors: Filipenko I, Schwalm S, Reali L, Pfeilschifter J, Fabbro D, Huwiler A, Zangemeister-Wittke U
- Issue date: 2016 Nov
- PROSTAGLANDIN E<sub>2</sub> stimulates cancer-related phenotypes in prostate cancer PC3 cells through cyclooxygenase-2.
- Authors: Madrigal-Martínez A, Constâncio V, Lucio-Cazaña FJ, Fernández-Martínez AB
- Issue date: 2019 May
- Activation of COX-2/PGE2 Promotes Sapovirus Replication via the Inhibition of Nitric Oxide Production.
- Authors: Alfajaro MM, Choi JS, Kim DS, Seo JY, Kim JY, Park JG, Soliman M, Baek YB, Cho EH, Kwon J, Kwon HJ, Park SJ, Lee WS, Kang MI, Hosmillo M, Goodfellow I, Cho KO
- Issue date: 2017 Feb 1