Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer

Author:

Lu, Weiqiang [ORCID]

Yu, Weiwei

He, Jiacheng

Liu, Wenjuan

Yang, Junjie

Lin, Xianhua

Zhang, Yuanjin

Wang, Xin [ORCID]

Jiang, Wenhao

Luo, Jian

Zhang, Qiansen

Yang, Huaiyu

Peng, Shihong

Yi, Zhengfang

Ren, Shancheng

Chen, Jing

Siwko, Stefan

Nussinov,Ruth

Cheng, Feixiong

Zhang, Hankun [ORCID]

Liu, Mingyao [ORCID]
Author Address

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China., Department of Urology, Changhai Hospital, Second Military University, Shanghai, China., School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China., Department of Molecular and Cellular Medicine, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, TX, USA., Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, MD, USA., Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel., Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, USA., Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.,

Abstract:

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. © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

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