Single-Cell Analysis Reveals EP4 as a Target for Restoring T-Cell Infiltration and Sensitizing Prostate Cancer to
Shihong Peng1, Pan Hu1, Yu-Tian Xiao2,3
1East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology; Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
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.
Insights
Researchers identified EP4 as a target for prostate cancer immunotherapy. Combining EP4 antagonist YY001 with anti-PD-1 antibody effectively treats unresponsive prostate tumors, leading to tumor regression and lasting immune memory.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immunotherapy shows promise for some cancers but fails in "cold" tumors like prostate cancer.
- Identifying novel targets is crucial for effective prostate cancer treatment.
Purpose of the Study:
- To identify a targetable marker for prostate cancer immunotherapy.
- To develop a novel immunotherapy targeting the identified marker.
Main Methods:
- Single-cell transcriptomic analysis of patient samples.
- Integrated analysis of RNA-sequencing datasets.
- In vitro and in vivo evaluation of EP4 antagonist YY001 combined with anti-PD-1 antibody.
Main Results:
- EP4 (PTGER4) is expressed in prostate cancer cells and immune cells, modulating the tumor immune microenvironment.
- YY001 inhibited myeloid-derived suppressor cells (MDSCs) and enhanced T cell anti-tumor functions.
- Combined therapy with YY001 and anti-PD-1 antibody reversed MDSC infiltration, increased CD8+ T cell activity, and reduced MDSC immunosuppression.
Conclusions:
- EP4 is a specific target for prostate cancer immunotherapy.
- YY001 synergizes with anti-PD-1 antibodies to induce significant tumor regression and lasting immunologic memory in unresponsive prostate cancers.
