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Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy
Pelly, Victoria S Moeini, Agrin Roelofsen, L. M. Bonavita, Eduardo Bell, Charlotte R Hutton, Colin Blanco-Gomez, Adrian Banyard, Antonia Bromley, Christian P Flanagan, Eimear
Pelly, Victoria S
Moeini, Agrin
Roelofsen, L. M.
Bonavita, Eduardo
Bell, Charlotte R
Hutton, Colin
Blanco-Gomez, Adrian
Banyard, Antonia
Bromley, Christian P
Flanagan, Eimear
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Abstract
Identifying strategies to improve the efficacy of immune checkpoint blockade (ICB) remains a major clinical need. Here, we show that therapeutically targeting the COX-2/PGE2/EP2-4 pathway with widely used non-steroidal and steroidal anti-inflammatory drugs synergized with ICB in mouse cancer models. We exploited a bilateral surgery model to distinguish responders from non-responders shortly following treatment and identified acute IFN-γ-driven transcriptional remodeling in responder mice, which was also associated with patient benefit to ICB. Monotherapy with COX-2 inhibitors or EP2-4 PGE2 receptor antagonists rapidly induced this response program and, in combination with ICB, increased the intratumoral accumulation of effector T cells. Treatment of patient-derived tumor fragments from multiple cancer types revealed a similar shift in the tumor inflammatory environment to favor T cell activation. Our findings establish the COX-2/PGE2/EP2-4 axis as an independent immune checkpoint and a readily translatable strategy to rapidly switch the tumor inflammatory profile from cold to hot.
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Date
2021
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Article
Citation
Pelly VS, Moeini A, Roelofsen LM, Bonavita E, Bell CR, Hutton C, et al. Anti-inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy. Cancer Discov. 2021 May 24;candisc.1815.2020.