Single-Cell Analysis Reveals EP4 as a Target for Restoring T-Cell Infiltration and Sensitizing Prostate Cancer to Immunotherapy.

Abstract

PURPOSE:

Immunotherapies targeting immune checkpoint molecules have shown promising treatment for a subset of cancers; however, many "cold" tumors, such as prostate cancer, remain unresponsive. We aimed to identify a potential targetable marker relevant to prostate cancer and develop novel immunotherapy.

EXPERIMENTAL DESIGN:

Analysis of transcriptomic profiles at single-cell resolution was performed in clinical patients' samples, along with integrated analysis of multiple RNA-sequencing datasets. The antitumor activity of YY001, a novel EP4 antagonist, combined with anti-programmed cell death protein 1 (PD-1) antibody was evaluated both in vitro and in vivo.

RESULTS:

We identified EP4 (PTGER4) as expressed in epithelial cells and various immune cells and involved in modulating the prostate cancer immune microenvironment. YY001, a novel EP4 antagonist, inhibited the differentiation, maturation, and immunosuppressive function of myeloid-derived suppressor cells (MDSC) while enhancing the proliferation and anticancer functions of T cells. Furthermore, it reversed the infiltration levels of MDSCs and T cells in the tumor microenvironment by overturning the chemokine profile of tumor cells in vitro and in vivo. The combined immunotherapy demonstrated a robust antitumor immune response as indicated by the robust accumulation and activation of CD8+ cytotoxic T cells, with a significantly decreased MDSC ratio and reduced MDSC immunosuppression function.

CONCLUSIONS:

Our study identified EP4 as a specific target for prostate cancer immunotherapy and demonstrated that YY001 inhibited the growth of prostate tumors by regulating the immune microenvironment and strongly synergized with anti-PD-1 antibodies to convert completely unresponsive prostate cancers into responsive cancers, resulting in marked tumor regression, long-term survival, and lasting immunologic memory.

• Authors: Shihong Peng, Pan Hu, Yu-Tian Xiao, Weiqiang Lu, Dandan Guo, Shixiu Hu, Jiayi Xie, Minna Wang, Weiwei Yu, Junjie Yang, Huang Chen, Xiaomin Zhang, Yasheng Zhu, Ye Wang, Yue Yang, Guanghui Zhu, Sujun Chen, Jian Wang, Bo Zhang, Weidong Chen, Huangan Wu, Zhenliang Sun, Tao Ding, Hankun Zhang, Zhengfang Yi, Mingyao Liu, Shancheng Ren
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 28 Issue 3 Pg. 552-567 (02 01 2022) ISSN: 1557-3265 [Electronic] United States
• PMID: 34740924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2021 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Immunological
• PDCD1 protein, human
• PTGER4 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, Prostaglandin E, EP4 Subtype

Topics

• Animals
• Antineoplastic Agents, Immunological (therapeutic use)
• CD8-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Gene Expression
• Humans
• Immunotherapy (methods)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Male
• Mice
• Molecular Targeted Therapy
• Programmed Cell Death 1 Receptor (immunology)
• Prostatic Neoplasms (immunology, therapy)
• Receptors, Prostaglandin E, EP4 Subtype (antagonists & inhibitors, genetics)
• Single-Cell Analysis
• Tumor Microenvironment (immunology)