Open AccessReprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer
Author(s) -
Lu Weiqiang,
Yu Weiwei,
He Jiacheng,
Liu Wenjuan,
Yang Junjie,
Lin Xianhua,
Zhang Yuanjin,
Wang Xin,
Jiang Wenhao,
Luo Jian,
Zhang Qiansen,
Yang Huaiyu,
Peng Shihong,
Yi Zhengfang,
Ren Shancheng,
Chen Jing,
Siwko Stefan,
Nussinov Ruth,
Cheng Feixiong,
Zhang Hankun,
Liu Mingyao
Publication year - 2020
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.202012798
Subject(s) - china , chinese academy of sciences , library science , reprogramming , biomedical sciences , biology , medicine , political science , computer science , genetics , pathology , cell , law
Immune checkpoint blockade (ICB) has a limited effect on colorectal cancer, underlining the requirement of co‐targeting the complementary mechanisms. Here, we identified prostaglandin E2 (PGE 2 ) receptor 4 (EP4) as the master regulator of immunosuppressive myeloid cells (IMCs), which are the major driver of resistance to ICB therapy. PGE 2 ‐bound EP4 promotes the differentiation of immunosuppressive M2 macrophages and myeloid‐derived suppressor cells (MDSCs) and reduces the expansion of immunostimulated M1 macrophages. To explore the immunotherapeutic role of EP4 signaling, we developed a novel and selective EP4 antagonist TP‐16. TP‐16 effectively blocked the function of IMCs and enhanced cytotoxic T‐cell‐mediated tumor elimination in vivo . Cell co‐culture experiments revealed that TP‐16 promoted T‐cell proliferation, which was impaired by tumor‐derived CD11b + myeloid cells. Notably, TP‐16 and anti‐PD‐1 combination therapy significantly impeded tumor progression and prolonged mice survival. We further demonstrated that TP‐16 increased responsiveness to anti‐PD‐1 therapy in an IMC‐related spontaneous colorectal cancer mouse model. In summary, this study demonstrates that inhibition of EP4‐expressing IMCs may offer a potential strategy for enhancing the efficacy of immunotherapy for colorectal cancer.