Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

Charlotte R. Bell, Victoria S. Pelly, Agrin Moeini, Shih-Chieh Chiang, Eimear Flanagan, Christian P. Bromley, Christopher Clark, Charles H. Earnshaw, Maria A. Koufaki, Eduardo Bonavita and Santiago Zelenay ()
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Charlotte R. Bell: The University of Manchester
Victoria S. Pelly: The University of Manchester
Agrin Moeini: The University of Manchester
Shih-Chieh Chiang: The University of Manchester
Eimear Flanagan: The University of Manchester
Christian P. Bromley: The University of Manchester
Christopher Clark: The University of Manchester
Charles H. Earnshaw: The University of Manchester
Maria A. Koufaki: The University of Manchester
Eduardo Bonavita: The University of Manchester
Santiago Zelenay: The University of Manchester

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract Cytotoxic 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.

Date: 2022
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DOI: 10.1038/s41467-022-29606-9

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