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COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor
Victor Prima1, Lyudmila N Kaliberova2, Sergey Kaliberov2
1Department of Urology, College of Medicine, University of Florida, Gainesville, FL 32610.
Abstract:
In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)-mediated inhibition of activated PD-1+ T lymphocytes plays a major role in tumor escape from immune system during cancer progression. Lately, the anti-PD-L1 and -PD-1 immune therapies have become an important tool for treatment of advanced human cancers, including bladder cancer. However, the underlying mechanisms of PD-L1 expression in cancer are not fully understood. We found that coculture of murine bone marrow cells with bladder tumor cells promoted strong expression of PD-L1 in bone marrow-derived myeloid cells. Tumor-induced expression of PD-L1 was limited to F4/80+ macrophages and Ly-6C+ myeloid-derived suppressor cells. These PD-L1-expressing cells were immunosuppressive and were capable of eliminating CD8 T cells in vitro. Tumor-infiltrating PD-L1+ cells isolated from tumor-bearing mice also exerted morphology of tumor-associated macrophages and expressed high levels of prostaglandin E2 (PGE2)-forming enzymes microsomal PGE2 synthase 1 (mPGES1) and COX2. Inhibition of PGE2 formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE2 pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE2 metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host.
Insights
Tumor cells induce programmed cell death protein ligand 1 (PD-L1) expression in myeloid cells via the COX2/mPGES1/prostaglandin E2 pathway. Inhibiting this pathway reduces PD-L1, offering a strategy to combat tumor immune evasion.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Programmed cell death protein 1 (PD-1) and its ligand PD-L1 are crucial in tumor immune evasion.
- Anti-PD-1/PD-L1 therapies are effective against advanced cancers like bladder cancer.
- Mechanisms regulating PD-L1 expression in cancer remain incompletely understood.
Purpose of the Study:
- To investigate the mechanisms underlying PD-L1 expression in bladder cancer.
- To identify pathways regulating PD-L1 in tumor-infiltrating myeloid cells.
- To explore therapeutic strategies targeting PD-L1 regulation.
Main Methods:
- Coculture of murine bone marrow cells with bladder tumor cells.
- Flow cytometry to identify PD-L1 expressing myeloid cell populations (F4/80+, Ly-6C+).
- In vitro assays to assess immunosuppressive activity of PD-L1+ cells.
- Pharmacological and genetic inhibition of prostaglandin E2 (PGE2) synthesis/degradation (COX2, mPGES1, 15-PGDH).
Main Results:
- Tumor cells induced PD-L1 expression in bone marrow-derived myeloid cells, specifically macrophages and myeloid-derived suppressor cells.
- PD-L1+ myeloid cells exhibited immunosuppressive properties, including CD8 T cell elimination in vitro.
- Tumor-infiltrating PD-L1+ cells showed features of tumor-associated macrophages and high PGE2-forming enzyme expression (mPGES1, COX2).
- Inhibition of PGE2 production (pharmacologically or genetically) significantly reduced PD-L1 expression.
Conclusions:
- The COX2/mPGES1/PGE2 pathway is a key regulator of PD-L1 expression in tumor-infiltrating myeloid cells.
- Reprogramming PGE2 metabolism in the tumor microenvironment can decrease immune suppression.
- Targeting the PGE2 pathway presents a potential therapeutic strategy to enhance anti-tumor immunity.
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