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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.

SUBMITTER: Pu D

PROVIDER: S-EPMC7952860 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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

Pu Dan D Yin Liyuan L Huang Lin L Qin Changlong C Zhou Yuwen Y Wu Qiang Q Li Yan Y Zhou Qinghua Q Li Lu L

Frontiers in oncology 20210226

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 E<sub>2</sub> (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 <i>v ...[more]

PMID: 33718229

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Project description:Chimeric antigen receptor T (CAR-T) cells targeting CD19 came into clinical practice for the treatment of B cell lymphoma in 2018. However, patients being treated for B cell lymphoma often suffer from comorbidities such as chronic pain, cardiovascular diseases and arthritis. Thus, these patients frequently receive concomitant medications that include nonsteroidal anti-inflammatory drugs (NSAIDs) like cyclooxygenase (COX) inhibitors. Celecoxib, a selective COX-2 inhibitor, and aspirin, a non-selective COX-1 and COX-2 inhibitor, are being used as anti-inflammatory, analgesic and anti-pyretic drugs. In addition, several studies have also focused on the anti-neoplastic properties of COX-inhibitors. As the influence of COX-inhibitors on CD19.CAR-T cells is still unknown, we investigated the effect of celecoxib and aspirin on the quantity and quality of CD19.CAR-T cells at different concentrations with special regard to cytotoxicity, activation, cytokine release, proliferation and exhaustion. A significant effect on CAR-T cells could be observed for 0.1 mmol/L of celecoxib and for 4 mmol/L of aspirin. At these concentrations, we found that both COX-inhibitors could induce intrinsic apoptosis of CD19.CAR-T cells showing a significant reduction in the ratio of JC-10 red to JC-10 green CAR-T cells from 6.46 ± 7.03 (mean ± SD) to 1.76 ± 0.67 by celecoxib and to 4.41 ± 0.32 by aspirin, respectively. Additionally, the ratios of JC-10 red to JC-10 green Daudi cells were also decreased from 3.41 ± 0.30 to 0.77 ± 0.06 by celecoxib and to 1.26 ± 0.04 by aspirin, respectively. Although the cytokine release by CD19.CAR-T cells upon activation was not hampered by both COX-inhibitors, activation and proliferation of CAR-T cells were significantly inhibited via diminishing the NF-ĸB signaling pathway by a significant down-regulation of expression of CD27 on CD4+ and CD8+ CAR-T cells, followed by a clear decrease of phosphorylated NF-ĸB p65 in both CD4+ and CD8+ CAR-T cells by a factor of 1.8. Of note, COX-inhibitors hampered expansion and induced exhaustion of CAR-T cells in an antigen stress assay. Collectively, our findings indicate that the use of COX-inhibitors is a double-edged sword that not only induces apoptosis in tumor cells but also impairs the quantity and quality of CAR-T cells. Therefore, COX-inhibitors should be used with caution in patients with B cell lymphoma under CAR-T cell therapy.

Project description:BackgroundThe emergence of cancer immunotherapies, notably immune checkpoint inhibitors, has revolutionized anti-cancer treatments. These treatments, however, have been reported to be effective in a limited range of cancers and cause immune-related adverse effects. Thus, for a broader applicability and enhanced responsiveness to solid tumor immunotherapy, immunomodulation of the tumor microenvironment is crucial. Transforming growth factor-β (TGF-β) has been implicated in reducing immunotherapy responsiveness by promoting M2-type differentiation of macrophages and facilitating cancer cell metastasis.MethodsIn this study, we developed macrophage membrane-coated nanoparticles loaded with a TGF-βR1 kinase inhibitor, SD-208 (M[Formula: see text]-SDNP). Inhibitions of M2 macrophage polarization and epithelial-to-mesenchymal transition (EMT) of cancer cells were comprehensively evaluated through in vitro and in vivo experiments. Bio-distribution study and in vivo therapeutic effects of M[Formula: see text]-SDNP were investigated in orthotopic breast cancer model and intraveneously injected metastasis model.ResultsM[Formula: see text]-SDNPs effectively inhibited cancer metastasis and converted the immunosuppressive tumor microenvironment (cold tumor) into an immunostimulatory tumor microenvironment (hot tumor), through specific tumor targeting and blockade of M2-type macrophage differentiation. Administration of M[Formula: see text]-SDNPs considerably augmented the population of cytotoxic T lymphocytes (CTLs) in the tumor tissue, thereby significantly enhancing responsiveness to immune checkpoint inhibitors, which demonstrates a robust anti-cancer effect in conjunction with anti-PD-1 antibodies.ConclusionCollectively, responsiveness to immune checkpoint inhibitors was considerably enhanced and a robust anti-cancer effect was demonstrated with the combination treatment of M[Formula: see text]-SDNPs and anti-PD-1 antibody. This suggests a promising direction for future therapeutic strategies, utilizing bio-inspired nanotechnology to improve the efficacy of cancer immunotherapy.

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

Publications

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

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