Editors' ChoiceCancer

Coaxing cancer control by modulating COX-2

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Science Translational Medicine  19 Jun 2019:
Vol. 11, Issue 497, eaax9566
DOI: 10.1126/scitranslmed.aax9566


Mouse models of pancreatic ductal adenocarcinoma respond to immunotherapy when given in combination with the cyclooxygenase-2 inhibitor celecoxib.

Over the last ten years, the introduction of immunotherapies, particularly immune checkpoint blockade (ICB), to routine clinical practice has revolutionized cancer treatment. In select cases, ICB can lead to remission and durable benefit for years. However, the resistance of many cancers—particularly pancreatic cancer—to ICB has limited broad use of the therapy. For effective ICB response, an amenable tumor microenvironment (TME) with sufficient T cell infiltration is generally necessary, but the factors contributing to efficacy are not fully clear. Strategies to improve ICB response are largely experimental but conceptually involve modifying the TME to improve immune recognition and infiltration.

To determine which tumor-intrinsic pathways might affect ICB response in pancreatic ductal adenocarcinoma (PDA), Markosyan et al. examined The Cancer Genome Atlas datasets. Upon finding that EPHA2 expression was most inversely correlated with CD8+ T cell presence, the authors knocked out Epha2 in a mouse model to recapitulate the human PDA microenvironment and found that T cell infiltration increased notably within the tumors compared with control. Transcriptional profiling of these tumors revealed that Ptgs2 was among the most highly differentially expressed genes, and comparison with human data confirmed that patients with decreased PTGS2 expression had improved survival. Knockdown of Ptgs2 with shRNA resulted in decreased tumor formation in mice. Ptgs2 protein, also known as cyclooxygenase-2 (COX-2), can also be inhibited by the COX-2 subclass of nonsteroidal anti-inflammatory drugs, such as celecoxib. The authors tested how PTGS2 inhibition with celecoxib might affect ICB response and found that combined celecoxib-ICB treatment resulted in significant tumor growth inhibition or even regression in the mice and, importantly, improved overall survival, concluding that PTGS2 inhibition sensitized PDA to ICB.

This work demonstrates the potential for COX-2 inhibition to improve cancer response to immunotherapy and merits consideration of clinical trials to test this finding. One important caveat is that COX-2 inhibitors have been linked to increased gastrointestinal bleeding and cardiac events, including death, so the safety profile of COX-2 in combination with ICB will have to be rigorously defined prior to broader clinical adoption.

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