COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells

Victor Prima, Lyudmila N. Kaliberova, Sergey Kaliberov, David T. Curiel, Sergei Kusmartsev

Research output: Contribution to journalArticlepeer-review

253 Scopus citations

Abstract

In recent years, it has been established that programmed cell death protein ligand 1 (PD-L1)-mediated inhibition of activated PD-1+ Tlymphocytes 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.

Original languageEnglish
Pages (from-to)1117-1122
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number5
DOIs
StatePublished - Jan 31 2017

Keywords

  • Bone marrow
  • Myeloid cells
  • PD-L1
  • PGEmetabolism
  • Tumor-associated macrophages

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