Reprogramming immunosuppressive myeloid cells facilitates immunotherapy for colorectal cancer. Issue 1 (7th December 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO molecular medicine. Volume 13:Issue 1(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: colorectal cancer -- immunosuppressive myeloid cells -- immunotherapy -- prostaglandin E2 receptor 4; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202012798
• Languages: English
• ISSNs: 1757-4676

Abstract

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. Synopsis: Immunosuppressive myeloid cells (IMCs) are a prominent driver of immunotherapy resistance in colorectal cancer. This study identifies EP4 as a master regulator of IMCs and highlights blockade of EP4 as a novel therapeutic strategy for enhancing immunotherapy in colorectal cancer. EP4 was identified as the main receptor of PGE2 enhancing the differentiation and expansion of immunosuppressive macrophages and MDSC. A novel EP4 antagonist, TP‐16, was designed and synthesized with high potency and selectivity, as well as favorable drug‐like properties. TP‐16 alone or in combination with PD‐1 antibody suppressed tumor growth in syngeneic mouse models and in the AOM/DSS‐induced colorectal cancer model. TP‐16‐induced EP4 inhibition boosted T cell‐mediated anti‐tumor immunity through targeting of the IMCs‐mediated immunosuppression in the tumor microenvironment. Abstract : Immunosuppressive myeloid cells (IMCs) are a prominent driver of immunotherapy resistance in colorectal cancer. This study identifies EP4 as a master regulator of IMCs and highlights blockade of EP4 as a novel therapeutic strategy for enhancing immunotherapy in colorectal cancer.