COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells
COX2/mPGES1/PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells
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COX2/mPGES1/PGE2通路调控肿瘤相关巨噬细胞和髓源性抑制细胞中PD-L1的表达
DOI：
10.1073/pnas.1612920114
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发表时间：
2017-01-31
影响因子：
11.1
通讯作者：
Kusmartsev, Sergei
中科院分区：
文献类型：
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作者：
Prima, Victor;Kaliberova, Lyudmila N.;Kusmartsev, Sergei
近年来发现，程序性细胞死亡蛋白配体1(PD-L1)介导的对活化的PD-1(+)T淋巴细胞的抑制在肿瘤发生发展过程中逃避免疫系统起重要作用。最近，抗PD-L1和-PD-1免疫疗法已成为治疗包括膀胱癌在内的晚期人类癌症的重要工具。然而，PD-L1在肿瘤中表达的潜在机制还不完全清楚。我们发现，小鼠骨髓细胞与膀胱肿瘤细胞共培养可促进骨髓来源的髓系细胞表达PD-L1。肿瘤诱导PD-L1的表达仅限于F4/80(+)巨噬细胞和Ly-6C(+)髓系来源的抑制细胞。这些表达PD-L1的细胞具有免疫抑制作用，并能在体外消除CD8T细胞。从荷瘤小鼠分离的肿瘤浸润性PD-L1(+)细胞也表现出肿瘤相关巨噬细胞的形态，并表达高水平的前列腺素E-2(PGE(2))形成酶微粒体PGE2合成酶1(MPGES1)和COX2。使用药物mPGES1和COX2抑制剂或基因过表达PGE2降解酶15-羟基前列腺素脱氢酶(15-PGDH)来抑制PGE2的形成，会导致PD-L1表达降低。综上所述，我们的研究表明，COX2/mPGES1/PGE2通路参与了肿瘤浸润性髓系细胞PD-L1表达的调节，因此，肿瘤微环境中PGE2代谢的重新编程为减轻肿瘤宿主的免疫抑制提供了机会。
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 E-2 (PGE(2))-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.