COX2/mPGES1/PGE ₂ pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

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 marrowderived 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 tumorassociated macrophages and expressed high levels of prostaglandin E 2 (PGE 2 )-forming enzymes microsomal PGE 2 synthase 1 (mPGES1) and COX2. Inhibition of PGE 2 formation, using pharmacologic mPGES1 and COX2 inhibitors or genetic overexpression of PGE 2 -degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), resulted in reduced PD-L1 expression. Together, our study demonstrates that the COX2/mPGES1/PGE 2 pathway involved in the regulation of PD-L1 expression in tumor-infiltrating myeloid cells and, therefore, reprogramming of PGE 2 metabolism in tumor microenvironment provides an opportunity to reduce immune suppression in tumor host.PD-L1 | tumor-associated macrophages | PGE 2 metabolism | myeloid cells | bone marrow

Celecoxib enhances the therapeutic efficacy of epirubicin for Novikoff hepatoma in rats

“…Celecoxib treatment also increases CD8 + CTL infiltration to tumor tissues via blocking of COX‐2‐IDO1 pathway . Moreover, recent study indicated celecoxib can inhibit immune checkpoint PD‐L1 in tumor microenvironment . From TCGA analysis, it was found COX‐2 expression was positively correlated with FOXP3 or CD68 expression in human HCC specimens ( n = 423) (Fig.…”

Progress in tumor-associated macrophage (TAM)-targeted therapeutics

“…Restoration of these nutrients by inhibiting arginase, nitric oxide synthase, and indoleamine 2, 3-dioxygenase (IDO) constitutes another promising therapeutic intervention to improve T cell survival and functions [136][137]. Moreover, TAMs are also known to mediate immunosuppressive and metastasis-promoting functions in response to cancer cell/TAM-secreted lipid metabolites such as prostaglandin E 2 (PGE 2 ) and sphingosine-1-phosphate (S1P) [138][139][140]. Pharmacological inhibition of PGE 2 -producing enzymes microsomal PGE 2 synthase 1 (mPGES1) and cyclooxygenase-2 (COX-2), with CAY10526 and celecoxib respectively, effectively reduced PGE 2 level in bone marrow cell/MBT-2 bladder cancer cell coculture with celecoxib being further shown to lower expression of T cell-suppressive programmed cell death ligand 1 (PD-L1) in an MBT-2 cancer model and also promote M2-to-M1 polarization of TAMs in an Apc min/+ colon cancer model [139][141].…”

Contribution of Adipose Tissue to Development of Cancer

“…Prima et al reported that coculture of bone marrow-derived myeloid cells with bladder tumor cells elevated production of PGE 2 by both MDSCs and TAMs, and induced expression of the PD-1 ligand, programmed death-1 ligand (PD-L1), in these populations in a PGE 2 -dependent manner (312). PD-1 and its ligands PD-L1 and PD-L2 were also more highly expressed in prostate tumors of obese mice compared to those from lean animals (457).…”