Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer

Weiqiang Lu*, Weiwei Yu, Jiacheng He, Wenjuan Liu, Junjie Yang, Xianhua Lin, Yuanjin Zhang, Xin Wang, Wenhao Jiang, Jian Luo, Qiansen Zhang, Huaiyu Yang, Shihong Peng, Zhengfang Yi, Shancheng Ren, Jing Chen, Stefan Siwko, Ruth Nussinov, Feixiong Cheng, Hankun Zhang*Mingyao Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 (PGE2) receptor 4 (EP4) as the master regulator of immunosuppressive myeloid cells (IMCs), which are the major driver of resistance to ICB therapy. PGE2-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.

Original languageEnglish
Article numbere12798
JournalEMBO Molecular Medicine
Issue number1
StatePublished - 11 Jan 2021


  • colorectal cancer
  • immunosuppressive myeloid cells
  • immunotherapy
  • prostaglandin E2 receptor 4


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