Targeting YAP-Dependent MDSC Infiltration Impairs Tumor Progression.

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Prostate cancer progression involves complex interactions between tumor cells and the immune microenvironment.
• Identifying key immune cell populations and signaling pathways is crucial for developing novel therapeutic strategies.

Purpose of the Study:

• To investigate the role of infiltrating immune cells in prostate cancer progression.
• To elucidate the signaling mechanisms driving the recruitment of immune cells to prostate tumors.
• To explore the therapeutic potential of targeting identified pathways in advanced prostate cancer.

Main Methods:

• Utilized a Pten/Smad4-driven prostate adenocarcinoma mouse model.
• Employed a dual reporter prostate cancer model for transcriptomic profiling.
• Investigated the role of myeloid-derived suppressor cells (MDSCs) and the CXCL5-CXCR2 signaling axis.
• Analyzed Hippo-YAP signaling pathway activation and its downstream effects.
• Correlated findings with clinicopathologic studies of human prostate tumors.

Main Results:

• Polymorphonuclear myeloid-derived suppressor cells (MDSCs) were identified as the major infiltrating immune cells, and their depletion blocked tumor progression.
• Cancer-secreted CXCL5 attracts CXCR2-expressing MDSCs, and pharmacologic inhibition of CXCR2 impeded tumor growth.
• Hyperactivated Hippo-YAP signaling drives CXCL5 upregulation and promotes MDSC recruitment via the YAP-TEAD complex.
• YAP1 upregulation and activation were observed in a subset of human prostate tumors, correlating with MDSC-related gene expression.

Conclusions:

• MDSCs play a critical role in prostate tumor progression.
• The Hippo-YAP pathway non-autonomously regulates CXCL5, a key mediator of MDSC recruitment.
• Targeting MDSCs or the CXCL5-CXCR2 signaling pathway offers a promising therapeutic strategy for advanced prostate cancer, eliciting robust antitumor responses and prolonging survival.