Abstract 5180: CXCR7 mediates an immune-suppressive tumor microenvironment and promotes prostate cancer progression
Authors: Hongshun Shi, Ziqi Zhang, Lourdes Brea, Zhuoyuan Lin, Viriya Keo, Sambhavi Senthil, BaoHan Thi Vo, Galina Gritsina, Xiaojun Kong, Jonathan Zhao, Haydn Thomas Kissick, Xiuwei Zhang, Jindan Yu
Journal: Cancer Research (2025)

Abstract Background: Genetic inactivation of Pten and/or TP53 are common in human cancers including advanced prostate cancer (PCa). We previously reported CXCR7 up-regulation in castration resistant prostate cancer (CRPC), following androgen-receptor-targeted therapies. However, how CXCR7 regulates PCa and the tumor immune microenvironment (TIME) is poorly understood. Methods: We generated PbCre:Pten/TP53/Cxcr7 (TKO) mice, which were compared to the PbCre:Pten/TP53 (DKO) mice. We performed histology analyses of the mice aged from 12 to 24 weeks and utilized scRNA-seq to analyze prostate samples collected from transgenic mice of 12- and 18-week age. Multiplexed error-robust fluorescence in situ hybridization (MERFISH) platform was used to further confirm our results and demonstrate a spatial relationship. In addition, Cy-Tek and FACS analysis were employed to explore the tumor microenvironment focusing on immune cells. We then analyzed publicly available human PCa datasets to explore the correlation of CXCR7 with immune cell subsets using CIBERSORT. Results: Prostate-specific deletion of Cxcr7 in the Pten/TP53-DKO mice resulted in significant delay in prostate tumor progression. We found differential enriched lymphoid cluster and decreased Spink1+ luminal and Tff3+ luminal clusters after Cxcr7 knockout. Cxcr7 deletion was associated with profound TIME remodeling characterized by increased CD8+ T cells and reduced Gr-1+CD11b+ myeloid-derived suppressor cells (MDSC). In addition, Cxcr7 knockout facilitated the invasion of CD4+ and CD8+ T cells into the tumors, while these immune cells were mainly located in the stroma of the prostates of the DKO mice. TKO mouse also exhibited enhanced cell-cell interactions with PCa, compared to the DKO mouse, characterized by a decrease of IL6 signaling and an increase of IFN-II and MHC-I signaling. Critically, examination of human PCa datasets confirmed that high levels of CXCR7 were indeed correlated with lower CD8+ T cell infiltration in the tumors. Conclusion: Cxcr7 deletion delayed prostate cancer progression caused by Pten/TP53 loss. Combining scRNA-seq with a spatial framework of gene expression analyses of transgenic mouse models, we demonstrated a critical role of CXCR7 in remodeling the tumor microenvironment. Our result indicates CXCR7 as a promising therapeutic target for Pten/TP53-deficient prostate cancer. Citation Format: Hongshun Shi, Ziqi Zhang, Lourdes Brea, Zhuoyuan Lin, Viriya Keo, Sambhavi Senthil, BaoHan Thi Vo, Galina Gritsina, Xiaojun Kong, Jonathan Zhao, Haydn Thomas Kissick, Xiuwei Zhang, Jindan Yu. CXCR7 mediates an immune-suppressive tumor microenvironment and promotes prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5180.