Cyclooxygenase-2 Inhibitor: A Potential Combination Strategy With Immunotherapy in Cancer

Abstract

The clinical application of immunotherapy is the milestone of cancer treatment. However, some patients have bad reaction. Cyclooxygenase-2 (COX-2) is frequently expressed in multiple cancer cells and is associated with poor prognosis. It is the key enzyme of prostaglandin E2 (PGE2) that has been proved to promote the development, proliferation and metastasis of tumor cells. Recent studies further find the PGE2 in tumor microenvironment (TME) actively triggers tumor immune evasion via many ways, leading to poor response of immunotherapy. COX-2 inhibitor is suggested to restrain the immunosuppression of PGE2 and may enhance or reverse the response of immune checkpoint inhibitors (ICIs). This review provides insight into the mechanism of COX-2/PGE2 signal in immunosuppressive TME and summarizes the clinical application and trials in cancer treatment.

The Inflammatory Profile of the Tumor Microenvironment, Orchestrated by Cyclooxygenase-2, Promotes Epithelial-Mesenchymal Transition

“…Other therapeutic strategies with promising prospects are using the association of COX-2 inhibitors and immune checkpoint blockade as a potential choice ( 147 ). Several clinical trials of COX-2 inhibitor combination therapy with immune checkpoint inhibitors in cancers have been described.…”

A Signaling View into the Inflammatory Tumor Microenvironment

“…Moreover, activated NF-κB also induces the expression of MMP-2 and MMP-9, again synergizing with STAT3 activity to facilitate EMT, invasion and metastasis [199,200]. NF-κB also regulates the expression of another important mediator of the inflammatory TME, often found overexpressed in malignant tumors-cyclooxygenase-2 (COX-2) [193,201].…”

“…COX-1 is constitutively expressed in a wide range of normal tissues and works as a housekeeping enzyme responsible for maintaining tissue homeostasis. COX-2 is nearly absent in most normal cells, but is often overexpressed in multiple cancers, including colorectal, breast, stomach, lung, and pancreatic cancers, and is associated with poor prognosis [201,203]. Of note, COX-2derived PGE2 has been shown to mediate the crosstalk between colonic tumor cells and TAMs [204], induce the accumulation and activation of MDSCs [205,206], and promote the tumor growth of mutant BRAFV600E melanomas by suppressing immunity and enhancing tumor-promoting inflammation [204,207,208].The depletion of COX-2 or downstream PGE2 synthases modifies the TME inflammatory signaling profile from pro-tumorigenic to anticancer pathways [193,201].…”

“…COX-2 is nearly absent in most normal cells, but is often overexpressed in multiple cancers, including colorectal, breast, stomach, lung, and pancreatic cancers, and is associated with poor prognosis [201,203]. Of note, COX-2derived PGE2 has been shown to mediate the crosstalk between colonic tumor cells and TAMs [204], induce the accumulation and activation of MDSCs [205,206], and promote the tumor growth of mutant BRAFV600E melanomas by suppressing immunity and enhancing tumor-promoting inflammation [204,207,208].The depletion of COX-2 or downstream PGE2 synthases modifies the TME inflammatory signaling profile from pro-tumorigenic to anticancer pathways [193,201]. Moreover, the inhibition of COX-2 synergizes with PD-1 blockade to improve tumor cell eradication and augment the numbers of functional tumorspecific CTLs in patients with advanced epithelial ovarian cancer [209].…”

“…HDAC6 upregulation in CAFs was a crucial epigenetic mediator to promote an immunosuppressive TME by regulating STAT3 activation and promoting STAT3-dependent expression of COX-2 and PGE2 synthesis [213]. Finally, the frequent cancer-associated aberrant activity of classical mitogen-activated protein kinase (MAPK) cascades, such as the MAPK/ERK and p38 MAPK pathways, also promoting the upregulation of COX-2/PGE2, thus favoring immunosuppressive TME and promoting the progression of various cancer types [201,[214][215][216].…”